Amorphous solid dispersions of dasatinib and uses thereof

ABSTRACT

Amorphous solid dispersions and pharmaceutical compositions of the protein kinase inhibitor dasatinib. The pharmaceutical compositions may be used in methods of treating a proliferative disorder such as cancer, or in methods of delivering dasatinib to patients without regard to whether the patient is concurrently administered a gastric acid-reducing agent, or without regard to whether the patient has an elevated gastric pH. The compositions may be particularly suitable for patients afflicted by achlorhydria or hypochlorhydria, or  Helicobacter pylori  infection.

REFERENCE TO RELATED APPLICATIONS

The present application is a continuation application of U.S.application Ser. No. 17/206,823, filed Mar. 19, 2021, which is acontinuation of International Application No. PCT/US2021/014742, filedJan. 22, 2021, which claims the benefit of U.S. Provisional App. No.62/965,650 (filed Jan. 24, 2020) and U.S. Provisional App. No.63/018,182 (filed Apr. 30, 2020); the entire disclosures of which arehereby incorporated by reference.

BACKGROUND

Protein kinase inhibitors (PKIs) have been studied for their potentialuse in treating various disorders of cellular proliferation, includingcancer. The potential for PKIs as a treatment is based on the role thatprotein kinases are known to play in regulating many cellular pathways,including those involved in signal transduction. Dysregulation ofprotein kinases has been implicated in the development and progressionof many cancers, which suggests that PKIs may be useful as a treatmentfor disorders or diseases such as cancer that are caused by uncontrolledoverexpression or upregulation of protein kinases.

One such PKI is dasatinib, which is currently marketed as animmediate-release formulation for oral administration under the brandname SPRYCEL. SPRYCEL is a pharmaceutical formulation of crystallinedasatinib monohydrate. SPRYCEL is indicated for the treatment of (a)adult patients with newly diagnosed Philadelphia chromosome-positive(Ph+) chronic myeloid leukemia (CML) in chronic phase; (b) adultpatients with chronic, accelerated, or myeloid or lymphoid blast phasePh+ CML with resistance or intolerance to prior therapy includingimatinib; (c) adult patients with Philadelphia chromosome-positive acutelymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to priortherapy; (d) pediatric patients one year of age and older with Ph+ CMLin chronic phase; and (e) pediatric patients one year of age and olderwith newly diagnosed Ph+ ALL in combination with chemotherapy.

Presently, oral dosage of SPRYCEL is known to be affected byco-administration with other drugs. For example, oral bioavailability ofSPRYCEL is strongly affected when co-administered with gastricacid-reducing agents such as H₂ antagonists (e.g., famotidine), protonpump inhibitors (e.g., omeprazole), or antacids. In particular, theprescribing information for SPRYCEL states that “[t]he coadministrationof SPRYCEL with a gastric acid reducing agent may decrease theconcentrations of dasatinib” and that “[d]ecreased dasatinibconcentrations may reduce efficacy.”

The aqueous solubility of dasatinib is pH-dependent. As a result, uponadministration the exposure (expressed as area-under-the-curve, or“AUC”) achieved by oral dosage of SPRYCEL can be reduced significantlywhen H₂ antagonists or proton pump inhibitors are used concomitantly bythe patient. Per the SPRYCEL prescribing information, the administrationof a single dose of SPRYCEL 10 hours following administration offamotidine (an H₂ antagonist) reduced the mean AUC of dasatinib by 61%;and the administration of a single 100 mg dose of SPRYCEL 22 hoursfollowing a 40 mg dose of omeprazole (a proton pump inhibitor) at steadystate reduced the mean AUC of dasatinib by 43%.

As a result of these clinical findings, the prescribing information forSPRYCEL warns, “[d]o not administer H₂ antagonists or proton pumpinhibitors with SPRYCEL.” The prescribing information further suggeststhat antacids (such as aluminum hydroxide/magnesium hydroxide) can beconsidered in place of H₂ antagonists or proton pump inhibitors, butsimultaneous administration of SPRYCEL with antacids is to be avoided;administration of an antacid should be at least 2 hours before and 2hours after the prescribed dose of SPRYCEL.

These restrictions on how patients can treat indigestion or excessgastric acidity while treated with SPRYCEL are burdensome, especially inlight of how often such symptoms can occur within the patientpopulation. Further, poor adherence to the prescribing information'swarnings about taking gastric acid-reducing agents while being treatedwith SPRYCEL can be detrimental to the patient. Thus, there remains aneed in the art for a dasatinib treatment that does not require apatient to avoid co-administration of a gastric acid-reducing agent.

As yet another shortcoming of the currently available dasatinib product,it is known that there is considerable inter- and intra-patientvariability in pharmacokinetic parameters with SPRYCEL. The highvariability may be due to several factors, including differences inabsorption, metabolism, elimination, or other variables. However, insome cases it is possible to reduce the variability of drug products byimproving the formulation by which they are administered.

SUMMARY OF DISCLOSURE

An aspect of the disclosure relates to an amorphous solid dispersion(“ASD”) comprising dasatinib. The present disclosure also relatespharmaceutical compositions comprising the ASDs, and to methods oftreatment involving the administration of the pharmaceuticalcompositions.

In some embodiments, the ASD or pharmaceutical composition isadministered without regard to whether the patient or subject isadministered a gastric acid-reducing agent. In some embodiments of themethods of the disclosure, the ASD or pharmaceutical composition isadministered to the patient or subject with a gastric acid-reducingagent. The gastric acid-reducing agent may be selected from an H₂antagonist, a proton pump inhibitor, or an antacid.

In some embodiments, the ASD or pharmaceutical composition isadministered without regard to whether the patient or subject haselevated gastric pH. In some embodiments, the ASD or pharmaceuticalcomposition is administered to a patient or subject with an elevatedgastric pH. In some embodiments, the condition by which the patient'sgastric pH is elevated is achlorhydria or hypochlorhydria. In someembodiments, the condition by which the patient's gastric pH is elevatedis infection by Helicobacter pylori.

A further aspect of the disclosure relates to treatment regimens fortreating a proliferative disorder in a patient in need thereof.

Additional aspects of the disclosure relate to a kit for sale to a user,the kit comprising a pharmaceutical composition and a package insert. Insome embodiments, the package insert informs the user that thepharmaceutical composition can be co-administered with a gastricacid-reducing agent. In some embodiments, the package insert does notcomprise a warning that the pharmaceutical composition should not beco-administered with H₂ antagonists or proton pump inhibitors. In someembodiments, the package insert informs the user that the pharmaceuticalcomposition can be suitably administered if the user has chronicallyelevated gastric pH. In some embodiments, the package insert informs theuser that the pharmaceutical composition can be suitably administered ifthe user has been diagnosed with or is afflicted by achlorhydria orhypochlorhydria. In some embodiments, the package insert informs theuser that the pharmaceutical composition can be suitably administered ifthe user has been diagnosed with or is afflicted by Helicobacter pyloriinfection.

In other aspects, the disclosure provides amorphous solid dispersionshaving a high drug load of dasatinib, in the range from 70% to 95%. Theamorphous solid dispersions of the disclosure are surprisingly stable atthese high drug loads.

In still another aspect, the present disclosure provides apharmaceutical composition that may achieve a reduced inter-subjectvariability and/or within-subject variability, as compared to thevariabilities observed for SPRYCEL.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows in vitro dissolution profiles of dasatinib dissolved inFasted State Simulated Gastric Fluid (FaSSGF) (pH 1.6) transitioned toFasted State Simulated Intestinal Fluid (FaSSIF) (pH 6.4) at t=30 min,for an ASD of dasatinib and EUDRAGIT L100-55 at a w/w ratio(Dasatinib:EUDRAGIT L100-55) of 60:40, for an ASD of dasatinib andEUDRAGIT E100 at a w/w ratio (Dasatinib:EUDRAGIT E100) of 50:50, and forSPRYCEL, as described in Example 3. Each data point represents the meanof three replicates.

FIG. 2 shows in vitro dissolution profiles of dasatinib dissolved inFaSSGF (pH 4.0) transitioned to FaSSIF (pH 6.4) at t=30 min, for an ASDof dasatinib and EUDRAGIT L100-55 at a w/w ratio (Dasatinib:EUDRAGITL100-55) of 60:40, for an ASD of dasatinib and EUDRAGIT E100 at a w/wratio (Dasatinib:EUDRAGIT E100) of 50:50, and for SPRYCEL, as describedin Example 3. Each data point represents the mean of three replicates.

FIG. 3 shows in vitro dissolution profiles of dasatinib dissolved inFaSSGF (pH 6.0) transitioned to FaSSIF (pH 6.4) at t=30 min, for an ASDof dasatinib and EUDRAGIT L100-55 at a w/w ratio (Dasatinib:EUDRAGITL100-55) of 60:40, for an ASD of dasatinib and EUDRAGIT E100 at a w/wratio (Dasatinib:EUDRAGIT E100) of 50:50, and for SPRYCEL, as describedin Example 3. Each data point represents the mean of three replicates.

FIG. 4 shows canine in vivo pharmacokinetic profiles resulting fromadministration of an ASD of dasatinib and EUDRAGIT L100-55 at a w/wratio (Dasatinib:EUDRAGIT L100-55) of 60:40, an ASD of dasatinib andEUDRAGIT E100 at a w/w ratio (Dasatinib:EUDRAGIT E100) of 50:50, andSPRYCEL, administered following pentagastrin pretreatment (pH 1-2), asdescribed in Example 4.

FIG. 5 shows canine in vivo pharmacokinetic profiles resulting fromadministration of an ASD of dasatinib and EUDRAGIT L100-55 at a w/wratio (Dasatinib:EUDRAGIT L100-55) of 60:40, an ASD of dasatinib andEUDRAGIT E100 at a w/w ratio (Dasatinib:EUDRAGIT E100) of 50:50, andSPRYCEL, following famotidine pretreatment (pH 6-8), as described inExample 4.

FIG. 6 shows human in vivo pharmacokinetic profiles resulting fromadministration of Dasatinib ASD Tablet and from administration ofSPRYCEL tablet following famotidine pretreatment (pH 5+), as describedin Example 5.

FIG. 7 shows human in vivo pharmacokinetic profiles resulting fromadministration of dasatinib ASD tablet and from administration ofSPRYCEL tablet under fasting conditions, and resulting fromadministration of Dasatinib ASD Tablet and from administration ofSPRYCEL tablet following famotidine pretreatment (pH 5+), as describedin Example 5.

FIG. 8 shows a box plot graphically representing the AUC data andcertain calculated statistical parameters from the studies described inExample 5.

FIG. 9 shows a box plot graphically representing the C_(max) data andcertain calculated statistical parameters from the studies described inExample 5.

FIG. 10 shows in vitro dissolution profiles obtained using a pH 4 buffer(Medium A) for tablets comprising Dasatinib:EUDRAGIT L100-55 ASDs andfor the SPRYCEL reference product, as detailed in Example 7.

FIG. 11 shows in vitro dissolution profiles obtained using a pH 4 buffer(Medium A) for tablets comprising Dasatinib:METHOCEL E5 ASDs and for theSPRYCEL reference product, as detailed in Example 7.

FIG. 12 shows in vitro dissolution profiles obtained using FeSSIF(Medium B) at pH 5.8 for tablets comprising Dasatinib:EUDRAGIT L100-55ASD at 60% and 80% drug load, for tablets comprising Dasatinib:METHOCELE5 ASD at 80% drug load, and for the SPRYCEL reference product, asdetailed in Example 7.

FIG. 13 shows in vitro dissolution profiles obtained using a pH 5.5buffer (Medium C) for tablets comprising Dasatinib:EUDRAGIT L100-55 ASDat 60% and 80% drug load, for tablets comprising Dasatinib:METHOCEL E5ASD at 80% drug load, and for the SPRYCEL reference product, as detailedin Example 7.

DETAILED DESCRIPTION

The present disclosure relates to dasatinib ASDs, pharmaceuticalcompositions of dasatinib ASDs, and methods of use involvingadministration of the dasatinib ASDs or pharmaceutical compositions. Thedasatinib ASDs and the pharmaceutical compositions of the presentdisclosure may provide particular advantages over standard commercial,immediate-release compositions of dasatinib, such as SPRYCEL. Forinstance, as described herein, the prescribing information for SPRYCELwarns to avoid co-administration with certain gastric acid-reducingagents, because such co-administration can negatively impact bloodconcentrations of dasatinib, resulting in a possible reduction inefficacy. In contrast, co-administration of the ASDs and pharmaceuticalcompositions of the disclosure with a gastric acid-reducing agentsurprisingly exhibits no such negative effect. As another advantage,pharmaceutical compositions of the disclosure may achieve a reducedinter-subject and/or intra-subject variability, as compared to thevariability observed for SPRYCEL.

Thus, dasatinib ASDs and pharmaceutical compositions of the presentdisclosure offer an advantageous presentation of dasatinib as comparedto the currently available commercial immediate-release product.

Dasatinib

Dasatinib is a tyrosine kinase inhibitor. The chemical name fordasatinib isN-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide.

Dasatinib has a molecular formula of C₂₂H₂₆ClN₇O₂S and is represented bythe following structure:

The molecular weight of dasatinib is 488.01 g/mol, while the molecularweight of dasatinib monohydrate is 506.02 g/mol.

SPRYCEL is a commercially available pharmaceutical formulation ofcrystalline dasatinib monohydrate, marketed in the United States underNew Drug Application 21-986. SPRYCEL is currently available asimmediate-release tablets containing 20 mg, 50 mg, 70 mg, 80 mg, 100 mg,or 140 mg dasatinib.

Dasatinib in crystalline forms is categorized as a BiopharmaceuticalClassification System (“BCS”) Class II (low solubility/highpermeability) compound. Dasatinib is known to exhibit pH-dependentaqueous solubility. Based on internal experimentation, the aqueoussolubility at pH 2 is approximately 1.4 mg/mL and drops rapidly withincreasing pH; at pH 6.2, the solubility is less than 1 μg/mL. Apreparation of dasatinib in a form that is intended to enhance itssolubility could increase its bioavailability. One approach forenhancing solubility is to produce an amorphous solid dispersion.

Amorphous Solid Dispersions of Dasatinib

One aspect of the present disclosure relates to amorphous soliddispersions (“ASDs”) comprising dasatinib and one or more polymers. Apharmaceutically suitable amorphous solid dispersion generally comprisesa pharmaceutically active ingredient, such as dasatinib, dispersed in apharmacologically inert carrier, such as a polymer. One aim of apharmaceutically suitable amorphous solid dispersion is to improve thebioavailability of the pharmaceutically active ingredient. Thisimprovement can occur, for example, because of enhanced surface area,improved wettability or dispersibility, increased dissolution rate, orother factors.

In general, it is favorable if the pharmaceutically active ingredient isdispersed in the polymer to form what has been termed in the art as a“glass solution.” However, other forms of dispersion, such as thosetermed as “solid solution” or “glass suspension,” may also be suitable.The precise characterization of the solid dispersion is not important,provided that the amorphous solid dispersion is capable of providingdesired characteristics and performance.

In the ASDs of the disclosure, the dasatinib may be as a free base or asa salt such as a hydrochloride. In some embodiments, the dasatinib is asa free base and is anhydrous. Such forms of dasatinib and processes ofpreparing dasatinib are disclosed, for example, in WO 2005/077945, WO2007/035874, WO 2009/053854, and WO 2015/181573. In the description ofthe amorphous solid dispersions and pharmaceutical compositions below,and in the claims, any reference to “dasatinib” refers broadly todasatinib free base, salts of dasatinib, anhydrous dasatinib (or saltsthereof), hydrates or solvates of dasatinib, and hydrates or solvates ofdasatinib salts as suitable alternatives, unless specified.

The one or more polymers, which should be pharmacologically inert,should be suitable to provide structure and stability to the ASD. By“pharmacologically inert,” it is meant that the material does notinitiate a pharmacological response or an adverse reaction whenintroduced to a relevant biological system (such as the gastrointestinaltract).

In some embodiments, the ASD comprises dasatinib and one or morepolymers. In certain embodiments, the ASD consists of dasatinib and theone or more polymers. In certain other embodiments, the ASD consistsessentially of dasatinib and the one or more polymers.

Polymers that can be used in the ASDs of the present disclosure mayinclude, but are not limited to, those described below. The term“polymer” includes, but is not limited to, organic homopolymers,copolymers (such as for example, block, graft, random, and terpolymers,etc.), and blends and modifications thereof. The term “copolymer” refersto polymers containing two or more different monomeric units orsegments, and includes terpolymers, tetrapolymers, etc.

Polymers that can be used in the ASDs of the present disclosure mayinclude ionizable or non-ionizable polymers, or a combination thereof.

In some embodiments, the one or more polymers may be non-ionizablepolymers. In certain embodiments, the ASD consists of dasatinib and oneor more non-ionizable polymers. In certain other embodiments, the ASDconsists essentially of dasatinib and one or more non-ionizablepolymers.

In some embodiments, the one or more polymers may be ionizable polymers.In certain embodiments, the ASD consists of dasatinib and one or moreionizable polymers. In certain other embodiments, the ASD consistsessentially of dasatinib and one or more ionizable polymers.

In yet other embodiments, a combination of ionizable and non-ionizablepolymers may be used. In certain embodiments, the ASD consists ofdasatinib and a combination of one or more non-ionizable polymers andone or more ionizable polymers. In certain other embodiments, the ASDconsists essentially of dasatinib and a combination of one or morenon-ionizable polymers and one or more ionizable polymers.

Polymers that can be used in the ASDs of the present disclosure mayinclude polymers that exhibit pH-dependent solubility, or polymers thatare generally insensitive to pH, or a combination thereof.

In some embodiments, the one or more polymers may exhibit pH-dependentsolubility. In certain embodiments, the ASD consists of dasatinib andone or more polymers that exhibits pH-dependent solubility. In certainother embodiments, the ASD consists essentially of dasatinib and one ormore polymers that exhibits pH-dependent solubility.

In other embodiments, the one or more polymers may be generallyinsensitive to pH. In certain embodiments, the ASD consists of dasatiniband one or more polymers generally insensitive to pH. In certain otherembodiments, the ASD consists essentially of dasatinib and one or morepolymers generally insensitive to pH.

In yet other embodiments, a combination of polymers may include one ormore polymers exhibiting pH-dependent solubility and one or morepolymers generally insensitive to pH. In certain embodiments, the ASDconsists of dasatinib and a combination of one or more polymersexhibiting pH-dependent solubility and one or more polymers generallyinsensitive to pH. In certain other embodiments, the ASD consistsessentially of dasatinib and a combination of one or more polymersexhibiting pH-dependent solubility and one or more polymers generallyinsensitive to pH.

Non-ionizable polymers. Suitable non-ionizable polymers may include:polysaccharides and polysaccharide derivatives (including celluloseethers and non-ionizable cellulose esters); polymers or copolymers ofN-vinylpyrrolidone and/or vinyl acetate; polymers of ethylene oxide;homopolymers or copolymers of lactic acid and/or glycolic acid; maleicanhydride copolymers; polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer; and poloxamers.

Suitable non-ionizable polysaccharides and polysaccharide derivativesmay include cellulose ethers and non-ionizable cellulose esters.Examples of suitable cellulose ethers include methylcellulose (“MC”;e.g., METHOCEL A15 LV, METHOCEL A4M), ethylcellulose (“EC”; e.g.,ETHOCEL), hypromellose or hydroxypropyl methylcellulose (“HPMC”; e.g.,METHOCEL E3, METHOCEL E5, METHOCEL E6, METHOCEL E15, AFFINISOL HPMCHME), hydroxyethyl cellulose (“HEC”; e.g., NATROSOL 250 Pharm), andhydroxypropyl cellulose (“HPC”; e.g., HPC EF, HPC LF, HPC JF, HPC L,KLUCEL).

Examples of non-ionizable cellulose esters that may be suitable includecellulose acetate, cellulose propionate, cellulose butyrate, andcellulose acetate butyrate.

Examples of suitable polymers or copolymers of N-vinylpyrrolidone and/orvinyl acetate include polyvinylpyrrolidone (“PVP”; e.g., PVP K25, PVPK90, VIVAPHARM PVP), crospovidone or crosslinked polyvinylpyrrolidone(e.g., KOLLIDON CL, VIVAPHARM PVPP), copovidone orvinylpyrrolidone/vinyl acetate copolymer (“PVP/VA”; e.g., KOLLIDON VA64, VIVAPHARM PVP/VA 64), and polyvinyl alcohol (“PVA”; e.g., VIVAPHARMPVA).

Examples of suitable polymers of ethylene oxide include polyethyleneglycol (“PEG”; e.g., KOLLISOLV PEG 8000) and poly(ethylene oxide)(“PEO”; e.g., POLYOX).

Examples of suitable homopolymers or copolymers of lactic acid and/orglycolic acid include polylactide or poly(lactic acid) (“PLA”),polyglycolide or poly(glycolic acid) (“PGA”), andpoly(lactic-co-glycolic acid) (“PLGA”).

Non-ionizable maleic anhydride copolymers such as poly(methyl vinylether/maleic anhydride) (“PVM/MA”) may also be suitable. Non-ionizablepoloxamers (e.g., PLURONIC, KOLLIPHOR) may also be suitable.

A polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graftcopolymer (e.g., SOLUPLUS) may also be a suitable non-ionizable polymer.

Ionizable polymers. Suitable ionizable polymers may be considered“anionic” or “cationic” polymers. Anionic and cationic polymers oftenexhibit pH-dependent solubility.

Anionic polymers often include carboxylate (such as acetate), phthalate,succinate, or acrylate functionalities. Anionic polymers are generallyinsoluble at low pH and more soluble at higher pH. Suitable anionicpolymers may include anionic polysaccharides and polysaccharidederivatives (such as ionizable cellulose esters), copolymers ofmethacrylic acid and/or alkyl acrylate, and derivatized vinyl acetatepolymers, for example.

An example of an ionizable polysaccharide that may be suitable isxanthan gum. Examples of suitable ionizable cellulose esters may includecarboxymethylcellulose (“CMC”; carboxymethylcellulose sodium),hypromellose acetate succinate, or hydroxypropyl methylcellulose acetatesuccinate (“HPMC-AS”; e.g., AFFINISOL HPMC-AS, AQUASOLVE, AQOAT),hydroxypropyl methylcellulose phthalate (“HPMC-P”; e.g., HP-50, HP-55),and cellulose acetate phthalate (“CAP”; e.g., EASTMAN C-A-P).

Suitable copolymers of methacrylic acid and/or alkyl methacrylate mayinclude methacrylic acid/methyl methacrylate copolymer (e.g., EUDRAGITL100) and methacrylic acid/ethyl acrylate copolymer (e.g., EUDRAGITL100-55, KOLLICOAT MAE).

An example of a derivatized vinyl acetate polymer that may be suitableis polyvinyl acetate phthalate (PVA-P; PHTHALAVIN).

Cationic polymers often include amine functionalities. Cationic polymersare generally soluble at low pH and less soluble at higher pH. Suitablecationic polymers may include cationic polysaccharides andpolysaccharide derivatives, and amine-functionalized copolymers ofmethacrylic acid and/or alkyl acrylate, for example.

An example of a cationic polysaccharide that may be suitable ischitosan.

Suitable amine-functionalized copolymers of methacrylic acid and/oralkyl acrylate include, for example, dimethylaminoethylmethacrylate/butyl methacrylate/methyl methacrylate copolymer (e.g.,EUDRAGIT E100) and aminoalkyl methacrylate copolymer such as poly(ethylacrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylatechloride (e.g., EUDRAGIT RL100, EUDRAGIT RL PO, EUDRAGIT RS PO).

In some embodiments, the one or more polymers comprise polymers that arecharacterized by pH-dependent solubility. In some embodiments, the oneor more polymers comprise an anionic polymer characterized bypH-dependent solubility. In some embodiments, the one or more polymerscomprise a copolymer of methacrylic acid and/or alkyl methacrylate. Insome embodiments, the one or more polymers comprise methacrylicacid/methyl methacrylate copolymer (e.g., EUDRAGIT L100) or methacrylicacid/ethyl acrylate copolymer (e.g., EUDRAGIT L100-55).

In some embodiments, the one or more polymers comprise methacrylic acidand ethyl acrylate copolymer. In certain embodiments, the polymerconsists of methacrylic acid/ethyl acrylate copolymer. In certainembodiments, the polymer consists essentially of methacrylic acid/ethylacrylate copolymer. In some embodiments, the ASD comprises dasatinib andmethacrylic acid/ethyl acrylate copolymer. In certain embodiments, theASD consists of dasatinib and methacrylic acid/ethyl acrylate copolymer.In certain other embodiments, the ASD consists essentially of dasatiniband methacrylic acid/ethyl acrylate copolymer. In certain embodiments,the ASD comprises anhydrous, free base dasatinib and methacrylicacid/ethyl acrylate copolymer. In certain embodiments, the ASD consistsof anhydrous, free base dasatinib and methacrylic acid/ethyl acrylatecopolymer. In certain embodiments, the ASD consists essentially ofanhydrous, free base dasatinib and methacrylic acid/ethyl acrylatecopolymer.

In any of the foregoing, the methacrylic acid/ethyl acrylate copolymercan be EUDRAGIT L100-55, for example. EUDRAGIT L100-55 is an anioniccopolymer demonstrating pH-dependent aqueous solubility. Generallyspeaking, EUDRAGIT L100-55 is largely insoluble in an aqueous medium atpH of 5 or lower, and largely soluble in an aqueous medium at pH 5.5 orgreater.

In other embodiments, the one or more polymers comprise a cationicpolymer characterized by pH-dependent solubility. In certainembodiments, the one or more polymers comprise an amine-functionalizedcopolymer of methacrylic acid and/or alkyl acrylate characterized bypH-dependent solubility.

In some embodiments, the one or more polymers comprisedimethylaminoethyl methacrylate/butyl methacrylate/methyl methacrylatecopolymer. In certain embodiments, the polymer consists ofdimethylaminoethyl methacrylate/butyl methacrylate/methyl methacrylatecopolymer. In certain embodiments, the polymer consists essentially ofdimethylaminoethyl methacrylate/butyl methacrylate/methyl methacrylatecopolymer. In some embodiments, the ASD comprises dasatinib anddimethylaminoethyl methacrylate/butyl methacrylate/methyl methacrylatecopolymer. In certain embodiments, the ASD consists of dasatinib anddimethylaminoethyl methacrylate/butyl methacrylate/methyl methacrylatecopolymer. In certain other embodiments, the ASD consists essentially ofdasatinib and dimethylaminoethyl methacrylate/butyl methacrylate/methylmethacrylate copolymer. In certain embodiments, the ASD comprisesanhydrous, free base dasatinib and dimethylaminoethyl methacrylate/butylmethacrylate/methyl methacrylate copolymer. In certain embodiments, theASD consists of anhydrous, free base dasatinib and dimethylaminoethylmethacrylate/butyl methacrylate/methyl methacrylate copolymer. Incertain embodiments, the ASD consists essentially of anhydrous, freebase dasatinib and dimethylaminoethyl methacrylate/butylmethacrylate/methyl methacrylate copolymer.

In any of the foregoing, the dimethylaminoethyl methacrylate/butylmethacrylate/methyl methacrylate copolymer can be EUDRAGIT E100, forexample. EUDRAGIT E100 is a cationic copolymer of dimethylaminoethylmethacrylate, butyl methacrylate, and methyl methacrylate in a 2:1:1:ratio, and demonstrates pH-dependent aqueous solubility. Generallyspeaking, EUDRAGIT E100 is largely soluble in an aqueous medium at pH of5 or lower, and largely soluble in an aqueous medium at pH 5.5 orgreater.

In some embodiments, the one or more polymers comprise polymers that aregenerally insensitive to pH. In some embodiments, the one or morepolymers may be non-ionizable polymers characterized that are generallyinsensitive to pH. In certain embodiments, the one or more polymers mayinclude non-ionizable polysaccharides and polysaccharide derivatives. Inyet other embodiments, the one or more polymers may include celluloseethers and non-ionizable cellulose esters.

In some embodiments, the one or more polymers comprise a hydroxypropylmethylcellulose (also known as “hypromellose” or “HPMC”). In certainembodiments, the one or more polymers consists of one or morehydroxypropyl methylcellulose polymers. In certain embodiments, the oneor more polymers consists essentially of one or more hydroxypropylmethylcellulose polymers. In some embodiments, the ASD comprisesdasatinib and one or more hydroxypropyl methylcellulose polymers. Incertain embodiments, the ASD consists of dasatinib and one or morehydroxypropyl methylcellulose polymers. In certain other embodiments,the ASD consists essentially of dasatinib and one or more hydroxypropylmethylcellulose polymers. In certain embodiments, the ASD comprisesanhydrous, free base dasatinib and one or more hydroxypropylmethylcellulose polymers. In certain embodiments, the ASD consists ofanhydrous, free base dasatinib and one or more hydroxypropylmethylcellulose polymers. In certain embodiments, the ASD consistsessentially of anhydrous, free base dasatinib and one or morehydroxypropyl methylcellulose polymers.

In any of the foregoing, the hydroxypropyl methylcellulose polymer canbe a suitable METHOCEL, such as METHOCEL E3, METHOCEL E5, METHOCEL E6,or METHOCEL E15, for example. These METHOCEL grades are non-ionizablewater-soluble cellulose ethers, characterized by a methoxyl substitutionof 28 to 30%, and a hydroxypropoxyl substitution of 7 to 12%. Thesegrades are characterized by a low solution viscosity (as determined at20° C. for a 2% solution in water, according to manufacturer'sspecifications), where the grade number indicates the midpoint of theviscosity range (e.g., METHOCEL E3 is characterized a viscosity of2.4-3.6 mPa·s; METHOCEL E5 is characterized a viscosity of 4.0-6.0mPa·s). These grades are considered low molecular-weight HPMC products,having a number average molecular weight (Mn) of about 20 kDa or lower.

While all these grades are suitable for use in the ASDs of thedisclosure, METHOCEL E5 has been demonstrated to be particularlysuitable. A combination or mixture of grades of hydroxypropylmethylcellulose may also be employed.

In some embodiments, the one or more polymers comprise a lowmolecular-weight hydroxypropyl methylcellulose. In certain embodiments,the one or more polymers consists of a low molecular-weighthydroxypropyl methylcellulose. In certain embodiments, the one or morepolymers consists essentially of a low molecular-weight hydroxypropylmethylcellulose. In any of the foregoing, METHOCEL E5 may beparticularly suitable.

In some embodiments, the one or more polymers comprise a lowmolecular-weight hydroxypropyl methylcellulose characterized by asolution viscosity of 4.0-6.0 mPa·s. In certain embodiments, the one ormore polymers consists of a low molecular-weight hydroxypropylmethylcellulose characterized by a solution viscosity of 4.0-6.0 mPa·s.In certain embodiments, the one or more polymers consists essentially ofa low molecular-weight hydroxypropyl methylcellulose characterized by asolution viscosity of 4.0-6.0 mPa·s. In any of the foregoing, METHOCELE5 may be particularly suitable.

In some embodiments of the ASD, the one or more polymers does notcomprise a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycolgraft co-polymer (e.g., SOLUPLUS). In some embodiments, the ASD issubstantially free from a polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft co-polymer. In some embodiments, theASD is essentially free from a polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft co-polymer. In some embodiments, theASD is free from a polyvinyl caprolactam-polyvinyl acetate-polyethyleneglycol graft co-polymer. In yet other embodiments, the ASD comprisesdasatinib and one or more polymers, with the proviso that the one ormore polymer is not a polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft co-polymer.

As used herein, the phrase “substantially free from” means that thestated component represents not more than 10% of the ASD, based onweight. The phrase “essentially free from” means that the statedcomponent represents not more than 5% of the ASD, based on weight. Theterm “free from” means that the stated component represents not morethan 2% of the ASD, based on weight.

In some embodiments of the ASD, the one or more polymers does notcomprise a polymer or copolymer of N-vinylpyrrolidone. In someembodiments, the ASD is free from a polymer or copolymer ofN-vinylpyrrolidone. In yet other embodiments, the ASD comprisesdasatinib and one or more polymers, with the proviso that the one ormore polymer is not a polymer or copolymer of N-vinylpyrrolidone. In theforegoing, the polymer or copolymer of N-vinylpyrrolidone can bepolyvinylpyrrolidone, crospovidone or crosslinked polyvinylpyrrolidone,copovidone or vinylpyrrolidone/vinyl acetate copolymer.

In some embodiments of the ASD, the one or more polymers does notcomprise a polyvinylpyrrolidone. In some embodiments, the ASD is freefrom a polyvinylpyrrolidone. In yet other embodiments, the ASD comprisesdasatinib and one or more polymers, with the proviso that the one ormore polymers is not a polyvinylpyrrolidone.

In some embodiments of the ASD, the one or more polymers does notcomprise a vinylpyrrolidone/vinyl acetate copolymer. In someembodiments, the ASD is free from a vinylpyrrolidone/vinyl acetatecopolymer. In yet other embodiments, the ASD comprises dasatinib and oneor more polymers, with the proviso that the one or more polymers is nota vinylpyrrolidone/vinyl acetate copolymer.

In the ASDs described in the disclosure, the amount of dasatinib ascompared to the amount of the one or more polymers may vary. Forexample, dasatinib and the one or more polymers may be present in a w/wratio (dasatinib:polymer) of 30:70 to 95:5. In some embodiments,dasatinib and the one or more polymers may be present in a w/w ratio of40:60 to 90:10. In other embodiments, dasatinib and the one or morepolymers may be present in a w/w ratio of 40:60 to 70:30. In someembodiments, dasatinib and the one or more polymers may be present in aratio of 70:30 to 95:5. In particular embodiments, the w/w ratio is30:70, 35:65, 40:60, 45:55, 50:50, 55:45, 60:40, 65:35, 70:30, 75:25,80:20, 85:15, 90:10, or 95:5.

While amorphous solid dispersions may exhibit enhanced solubility in abiorelevant fluid, the proportion of active ingredient in the amorphoussolid dispersion in the particles is usually limited, due to stabilityissues. Generally, the active ingredient tends toward its morethermodynamically stable crystalline form, so stable amorphous soliddispersions having a high proportion of active ingredient are uncommon.However, an amorphous solid dispersion having a higher proportion ofactive ingredient is desirable, because the apparent solubility may beenhanced (compared to an amorphous solid dispersion having a lowerproportion). Another benefit of having a higher proportion of activeingredient in the amorphous solid dispersion is that an overall smallerdosage form can be achieved, due to the inclusion of a lesser amount ofinactive ingredients. Accordingly, the disclosure further providesamorphous solid dispersions having a high drug load of dasatinib. Inthese embodiments, the dasatinib and the one or more polymers may bepresent in a ratio of 70:30 to 95:5. In particular embodiments, the w/wratio is 70:30, 75:25, 80:20, 85:15, 90:10, or 95:5. Such embodimentswere surprisingly found to have an unexpectedly high degree of chemicaland physical stability.

In some embodiments, the ASDs consist of dasatinib and one or morepolymers. In some embodiments, the ASDs consist essentially of dasatiniband one or more polymers. In other embodiments, the ASDs of the presentdisclosure may additionally comprise one or more other pharmaceuticallyacceptable functional components, such as one or more antioxidants,wetting agents, or solubilizers.

As used herein, the phrase “pharmaceutically acceptable” means that thecomponent does not initiate a pharmacological response or an adversereaction when introduced to a relevant biological system. By way ofnon-limiting example only, a substance found in the U.S. Food & DrugAdministration's “Generally Recognized as Safe” (“GRAS”) list, or asubstance used in accordance with guidelines in its Inactive IngredientDatabase, would be considered pharmaceutically acceptable. Similarly, asubstance in a corresponding database or list maintained by a parallelregulatory body, such as the European Medicines Agency, would beconsidered pharmaceutically acceptable. In general, in thepharmaceutical compositions of the disclosure, it is desirable to employonly components that do not cause an unacceptable level of physical orchemical instability in the resulting composition.

Examples of antioxidants that that may be used in the ASDs of thepresent disclosure include, but are not limited to, acetylcysteine,ascorbyl palmitate, butylated hydroxyanisole (“BHA”), butylatedhydroxytoluene (“BHT”), monothioglycerol, potassium nitrate, sodiumascorbate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodiumbisulfite, vitamin E or a derivative thereof, propyl gallate,ethylenediaminetetraacetic acid (“EDTA”) (e.g., disodium edetate),diethylenetriaminepentaacetic acid (“DTPA”), bismuth sodiumtriglycollamate, or a combination thereof. Antioxidants may alsocomprise amino acids such as methionine, histidine, cysteine and thosecarrying a charged side chain, such as arginine, lysine, aspartic acid,and glutamic acid. Any stereoisomer (e.g., l-, d-, or a combinationthereof) of any particular amino acid (e.g., methionine, histidine,arginine, lysine, isoleucine, aspartic acid, tryptophan, threonine andcombinations thereof) or combinations of these stereoisomers, may bepresent so long as the amino acid is present either in its free baseform or its salt form.

In some embodiments, the one or more antioxidants comprise BHT. In someembodiments, the one or more antioxidants comprise propyl gallate. Insome embodiments, the one or more antioxidants consist essentially ofBHT. In some embodiments, the one or more antioxidants consistessentially of propyl gallate. In some embodiments, the one or moreantioxidants consist of BHT. In some embodiments, the one or moreantioxidants consist of propyl gallate.

The one or more antioxidants may be present in the ASDs in an amount of0.001% to 2.0%, or 0.005% to 1.5%, or 0.01% to 1.0%, or 0.05% to 0.5%,by weight. Examples of the amount of the one or more antioxidants in theASDs include 0.001%, or 0.003%, or 0.005%, or 0.008%, or 0.01%, or0.015%, or 0.02%, or 0.025%, or 0.03%, or 0.035%, or 0.04%, or 0.05%, or0.075%, or 0.1%, or 0.2%, or 0.25%, or 0.3%, or 0.4%, or 0.5%, or 0.75%,or 1.0%, or 1.5%, or 2.0%, by weight.

A variety of pharmaceutically acceptable wetting agents may be included.As a non-limiting example of a wetting agent, poloxamers, such aspoloxamer 407 (e.g., PLURONIC F-127) or poloxamer 188 (e.g., PLURONICF-68), may be suitable. Other known pharmaceutically acceptable wettingagents may be suitably employed. A wetting agent may be included in theASD in an amount of 0.5% to 10%, or 1% to 8%, or 2% to 6%, by weight.

A variety of pharmaceutically acceptable solubilizers may be included.Non-limiting examples of suitable solubilizers include vitamin E TPGS(D-α-tocopherol polyethylene glycol succinate), SLS (sodium laurylsulfate), and docusate sodium. Other known pharmaceutically acceptablesolubilizers may be suitably employed. A solubilizer may be included inthe ASD in an amount of 0.1% to 10%, or 0.25% to 5%, or 0.5 to 1%, byweight.

In some embodiments, the ASDs comprise dasatinib, one or more polymers,and one or more antioxidants. In some embodiments, the ASDs consistessentially of dasatinib, one or more polymers, and one or moreantioxidants. In certain embodiments, the ASDs consist of dasatinib, oneor more polymers, and one or more antioxidants.

In some embodiments, the ASDs comprise dasatinib, methacrylic acid/ethylacrylate copolymer (such as EUDRAGIT L100-55), and propyl gallate. Incertain embodiments, the ASDs consist essentially of dasatinib, amethacrylic acid and ethyl acrylate copolymer such as EUDRAGIT L100-55,and propyl gallate. In certain embodiments, the ASDs consist ofdasatinib, methacrylic acid/ethyl acrylate copolymer (such as EUDRAGITL100-55), and propyl gallate. In particular embodiments, the ASDsconsist of dasatinib, methacrylic acid/ethyl acrylate copolymer (such asEUDRAGIT L100-55), and propyl gallate at a level of 0.1-0.5%, by weightof the ASD. In a particular embodiment, the ASD consists of an 80:20ratio of dasatinib, methacrylic acid/ethyl acrylate copolymer (such asEUDRAGIT L100-55), and propyl gallate at a level of 0.1-0.5% by weightof the ASD.

In some embodiments, the ASDs comprise dasatinib, dimethylaminoethylmethacrylate/butyl methacrylate/methyl methacrylate copolymer (such asEUDRAGIT E100), and propyl gallate. In certain embodiments, the ASDsconsist essentially of dasatinib, dimethylaminoethyl methacrylate/butylmethacrylate/methyl methacrylate copolymer (such as EUDRAGIT E100), andpropyl gallate. In certain embodiments, the ASDs consist of dasatinib,dimethylaminoethyl methacrylate/butyl methacrylate/methyl methacrylatecopolymer (such as EUDRAGIT E100), and propyl gallate. In particularembodiments, the ASDs consist of dasatinib, dimethylaminoethylmethacrylate/butyl methacrylate/methyl methacrylate copolymer (such asEUDRAGIT E100), and propyl gallate at a level of 0.1-0.5%, by weight ofthe ASD. In a particular embodiment, the ASD consists of a 60:40 ratioof dasatinib, dimethylaminoethyl methacrylate/butyl methacrylate/methylmethacrylate copolymer (such as EUDRAGIT E100), and propyl gallate at alevel of 0.1-0.5% by weight of the ASD.

In some embodiments, the ASDs comprise dasatinib, hydroxypropylmethylcellulose (such as METHOCEL E3 or METHOCEL E5), and propylgallate. In certain embodiments, the ASDs consist essentially ofdasatinib, hydroxypropyl methylcellulose (such as METHOCEL E3 orMETHOCEL E5), and propyl gallate. In certain embodiments, the ASDsconsist of dasatinib, hydroxypropyl methylcellulose (such as METHOCEL E3or METHOCEL E5), and propyl gallate. In particular embodiments, the ASDsconsist of dasatinib, hydroxypropyl methylcellulose (such as METHOCEL E3or METHOCEL E5), and propyl gallate at a level of 0.1-0.5%, by weight ofthe ASD. In a particular embodiment, the ASD consists of an 80:20 ratioof dasatinib, hydroxypropyl methylcellulose (such as METHOCEL E3 orMETHOCEL E5), and propyl gallate at a level of 0.1-0.5% by weight of theASD.

As used herein, the phrase “drug load” refers to the ratio (by weight %)of dasatinib in an ASD to the total solids weight of the ASD. By way ofexample, for an ASD consisting of dasatinib and a polymer, a 1:1 w/wratio of dasatinib:polymer would represent a 50% drug load; a 4:1 w/wratio of dasatinib:polymer would represent an 80% drug load, etc. As asecond example, an ASD comprising 40% dasatinib by weight, 50% polymerby weight, and 10% by weight of other pharmaceutically acceptablefunctional components would have a drug load of 40%.

The drug load of dasatinib in the ASDs of the present disclosure maysuitably range from 25% to 95%, or 30% to 90%, or 40% to 90%, or 40% to70%. Examples of the drug load of dasatinib in the ASDs include 25%, or30%, or 35%, 40%, or 45%, or 50%, or 55%, or 60%, or 65%, or 70%, or75%, or 80%, or 85%, or 90%, or 95%.

In particular embodiments, the present disclosure provides amorphoussolid dispersions having a high drug load of dasatinib, in the rangefrom 70% to 95%. The amorphous solid dispersions of the disclosure aresurprisingly stable at these high drug loads. The amorphous soliddispersions provide an enhanced apparent solubility in a biorelevantfluid, and therefore may provide an enhanced in vivo bioavailability.Another benefit of the high drug load amorphous solid dispersion is thatan overall smaller dosage form may be possible, due to the inclusion ofa lesser amount of inactive ingredients.

For the high drug load embodiments of the ASDs of the presentdisclosure, the drug load may suitably range from 70% to 95%, or 75% to95%, or 80% to 90%. Examples of the drug load of dasatinib in theamorphous solid dispersions include 70%, or 75%, or 80%, or 85%, or 90%,or 95%.

The dasatinib ASDs may be in the form of particles. In some embodiments,the particles do not comprise a surfactant. In other embodiments, theparticles do not comprise a wetting agent. In yet other embodiments, theparticles do not comprise a solubilizer. In other embodiments, theparticles comprise neither a surfactant nor a solubilizer. In otherembodiments, the particles are free from surfactants, wetting agents,and solubilizers. In other embodiments, the particles consist of polymerand dasatinib, and no additional functional components.

Particles of the ASDs of the disclosure may generally comprise theshapes of spheroids. As measured by conventional light scattering orlaser diffraction techniques, the diameter of the particles maygenerally range from about 0.05 μm to about 100 μm. The median diameter(D50 or Dv0.5) of the particle distribution may be in the range from 0.2μm to 60 μm, or 0.5 μm to 50 μm, or 0.5 μm to 40 μm.

In some embodiments, the median diameter of the particle distributionmay be from 1 μm to 40 μm, or from 2 μm to 25 μm, or from 3 μm to 20 μm.By way of example only, such particle size distributions can be achievedby known methods of spray drying.

In some embodiments, the median diameter of the particles may be from0.1 μm to 10 μm, or from 0.2 μm to 5 μm, or from 0.5 μm to 2 μm. By wayof example only, such particle size distributions can be achieved bymethods involving electrospraying, discussed further below.

The dasatinib ASDs of the present disclosure may demonstrate a desirablelevel of physical and/or chemical stability, which can be assessed bydifferent measures. Stability is generally assessed using conventionalanalytical techniques commonly known in pharmaceutical sciences.

Physical and chemical stability is generally assessed after storageunder controlled, elevated environmental conditions (“acceleratedconditions”) over a specified period of time. The storage conditions maybe one or more of 25° C./60% relative humidity (“RH”), or 25°C./protected, or 30° C./65% RH, or 40° C./75% RH, or 40° C./protected,or 50° C./80% RH. (As used herein in this context, “protected” meanssamples were sealed in foil pouches and placed in a controlled chamberfor the storage period). The period of time may be one or more of 1week, or 2 weeks, or 4 weeks or 1 month, or 2 months, or 3 months, or 4months, or 6 months, or 9 months, or 12 months, or 15 months, or 18months, or 21 months, or 24 months, or any period of time therebetween.

The dasatinib ASDs may demonstrate stability by having a particularassay value or a particular level of total related substances (e.g.,impurities), as measured by high performance liquid chromatography(“HPLC”), after storage under accelerated conditions over a specifiedperiod of time. The assay value is generally presented as a percentageof the quantity of analyte (e.g., dasatinib) detected relative to thequantity expected, with 100% is a favorable result and large deviationsfrom 100% are unfavorable. The total related substances is generallypresented as a percentage relative to the total quantity of substancesdetected (i.e., analyte plus impurities), where near 0% is favorable andlarge deviations from 0% are unfavorable.

In some embodiments, the dasatinib ASDs may have an assay as measured byHPLC of at least 90%, or at least 93%, or at least 95%, or at least 97%,or at least 98%, or at least 99%. In some embodiments, the dasatinibASDs may have a level of total related substances as measured by HPLC ofno more than 3%, or no more than 2.5%, or no more than 2%, or no morethan 1.5%, or no more than 1%, or no more than 0.9%, or no more than0.8%, or no more than 0.7%, or no more than 0.6%, or no more than 0.5%.

In some embodiments, the dasatinib ASDs may have an assay as measured byHPLC of at least 90%, or at least 93%, or at least 95%, or at least 97%,or at least 98%, after storage at 25° C./60% RH for 1 month, or 2months, or 3 months, or 6 months. In some embodiments, the dasatinibASDs may have a level of total related substances as measured by HPLC ofno more than 1.5%, or no more than 1%, or no more than 0.9%, or no morethan 0.8%, or no more than 0.7%, or no more than 0.6%, or no more than0.5%, after storage at 25° C./60% RH for 1 month, or 2 months, or 3months, or 6 months.

In some embodiments, the dasatinib ASDs may have an assay as measured byHPLC of at least 85%, or at least 90%, or at least 93%, or at least 95%,or at least 96%, or at least 97%, or at least 98%, or at least 99%,after storage at 40° C./75% RH for 1 month, or 2 months, or 3 months, or6 months. In some embodiments, the dasatinib ASDs may have a level oftotal related substances as measured by HPLC of no more than 2%, or nomore than 1.5%, or no more than 1%, or no more than 0.9%, or no morethan 0.8%, or no more than 0.7%, or no more than 0.6%, or no more than0.5%, after storage at 40° C./75% RH for 1 month, or 2 months, or 3months, or 6 months.

Stability may be also assessed by evaluating changes in glass transitiontemperature of the dasatinib ASDs under different storage conditionsover time. Glass transition temperature can be evaluated by modulatedDSC (“mDSC”) using conventional techniques. In some embodiments, the ASDis characterized by a single glass transition, the transition observedin the range from 25° C. to 200° C., or more suitably from 40° C. to150° C., by mDSC. In other embodiments, the ASD is characterized by morethan one transition, the transitions observed in the range from 25° C.to 200° C., or more suitably from 40° C. to 150° C., by mDSC.

In some embodiments, the glass transition temperature as measured bymDSC does not change by more than 5° C., or more than 4° C., or no morethan 3° C., after storage at 25° C./60% RH for 1 month, or 2 months, or3 months, or 6 months. In some embodiments, the glass transitiontemperature as measured by mDSC does not change by more than 6° C., ormore than 5° C., or more than 4° C., or more than 3° C., or more than 2°C., or no more than 1° C., after storage at 40° C./75% RH for 1 month,or 2 months, or 3 months, or 6 months.

Further, stability may be assessed by evaluating changes incrystallinity of the dasatinib ASDs under different storage conditionsover time, such as by suitable conventional powder x-ray diffractiontechniques (referred to herein as XRD). In the practice of the presentdisclosure, it is preferred (but not required) that the dasatinib ASDremains amorphous or essentially amorphous. In some embodiments,“amorphous” may be defined as having no detectable crystallinity asdetermined using methods known in the art, for instance, by using XRD.An example of using XRD to determine amorphicity is provided in Example1.

In some embodiments, “amorphous” may be defined as having a percentcrystallinity of no more than 5%, or no more than 4%, or no more than3%, or no more than 2%, or no more than 1%, as determined by XRD. Insome embodiments, “essentially amorphous” may be defined as having apercent crystallinity of no more than 8%, or no more than 7%, or no morethan 6%, as measured by XRD.

The ASDs of the disclosure may be amorphous or essentially amorphouswhen analyzed promptly after preparation, i.e., at t=0. For thesepurposes, the phrase “promptly after preparation” means that the ASD isanalyzed within a few days after preparation, and stored under protectedconditions at ambient temperature and humidity after preparation andbefore analysis.

The ASDs may be amorphous or essentially amorphous after storage undervarious storage conditions (e.g., 25° C./60% RH, 25° C./protected, 40°C./75% RH, 40° C./protected, 50° C./80% RH, etc.) for a period of atleast 1 week, or a period of at least 2 weeks, or a period of at least 3weeks, or a period of at least 4 weeks or 1 month, or a period of atleast 2 months, or a period of at least 3 months, or a period of atleast 4 months, or a period of at least 5 months, or a period of atleast 6 months, or a period of at least 7 months, or a period of atleast 8 months, or a period of at least 9 months, or a period of atleast 10 months, or a period of at least 11 months, or a period of atleast 12 months or 1 year. In some embodiments, the ASDs of thedisclosure may be amorphous or essentially amorphous under conditions ofhigh temperature and humidity (e.g., 40° C./75% RH) for a period of atleast 1 month, or a period of at least 2 months, or a period of at least3 months, or a period of at least 6 months.

The dasatinib ASDs of the present disclosure can be characterized forwater content, such as by using standard Karl Fischer coulometrictitration methods. In some embodiments, the dasatinib ASDs may comprisea water content as assessed by Karl Fischer coulometric titration methodof no more than 3%, or no more than 2.5%, or no more than 2%, or no morethan 1.5%, or no more than 1%.

In some embodiments, the dasatinib ASDs may comprise a water content asassessed by Karl Fischer coulometric titration method of no more than8%, or no more than 7%, or no more than 6%, or no more than 5%, or nomore than 4.5%, or no more than 4%, or no more than 3.5%, or no morethan 3%, or no more than 2.5%, or no more than 2%, or no more than 1.5%,or no more than 1%, after storage at 25° C./60% RH for 1 month, or 2months, or 3 months, or 6 months. In some embodiments, the dasatinibASDs may comprise a water content as assessed by Karl Fischercoulometric titration method of no more than 8%, or no more than 7%, orno more than 6%, or no more than 5%, or no more than 4.5%, or no morethan 4%, or no more than 3.5%, or no more than 3%, or no more than 2.5%,or no more than 2%, after storage at 40° C./75% RH for 1 month, or 2months, or 3 months, or 6 months.

Methods of Making Amorphous Solid Dispersions

The dasatinib ASDs of the present disclosure may be prepared by avariety of methods known in the art. Suitable methods generally includemixing, dissolving, or compounding the dasatinib and the one or morepolymers and, if present, one or more other functional components (suchas antioxidants, wetting agents, or solubilizers) to integrate thevarious components. In the practice of the various methods, thedasatinib may be introduced as dasatinib free base, or as a salt ofdasatinib, or as a solvate or hydrate of dasatinib.

Suitable methods are generally known in the art, and include kneading,co-grinding, melting, melt extrusion, melt agglomeration, dropping, andthe like. After the integration step, the material can be furtherprocessed by drying, grinding or crushing, sieving, etc.

In the practice of certain methods, dasatinib and the one or morepolymers (and other functional components, if present) may be mixed ordissolved with one or more solvents to provide a liquid feedstock.Suitable solvents may include, but are not limited to, water; analcohol, such as ethanol, methanol, propanol or isopropanol; an ether,such as ethyl ether or methyl tert-butyl ether; acetonitrile;tetrahydrofuran or methyl tetrahydrofuran; an acetate, such as methylacetate or ethyl acetate; a ketone, such as acetone or 2-butanone(methyl ethyl ketone, or “MEK”); toluene; ethyl formate; 1,4-dioxane;dimethylsulfoxide; N-methyl 2-pyrrolidone; volatile halogenated solventssuch as chloroform or dichloromethane; and combinations thereof. Themixing or dissolving of these contents may be by methods known in theart. For example, the contents may be mixed by manually mixing, or maybe mixed with a mixing device continuously, periodically, or acombination thereof. Examples of mixing devices may include, but are notlimited to, a magnetic stirrer, shaker, a paddle mixer, homogenizer, andany combination thereof.

After the dasatinib and the one or more polymers (and other functionalcomponents, if present) are mixed, the liquid feedstock may be formedinto an ASD, such as through solvent evaporation, lyophilization,precipitation or co-precipitation, spray drying, electrospraying,supercritical fluid extraction, etc. These methods are known andcommonly understood in the art.

In certain embodiments of the disclosure, the liquid feedstock may beformed into an ASD through electrospraying. Electrospraying, which hasalso been referred to as electrohydrodynamic atomization, has been usedto produce amorphous solid dispersion particles on a micron orsub-micron scale from suitable liquid feedstocks.

In one suitable electrospraying technique, the liquid feedstock isemitted through one or more nozzles toward a substrate in the presenceof an electric potential applied between the nozzles and the substrate.The liquid feedstock experiences electrical shear stress due to theapplied potential. When the shear stress overcomes the surface tensionof the liquid feedstock, droplets are emitted from the tips of thenozzles.

Conditions are controlled such that a cone jet of droplets is emitted atthe tip of the nozzles. The droplets take on an electric charge andrepel one another, which prevents their coagulation and promotesself-dispersion. The charged droplets accelerate toward the substrate asa result of the applied electric field.

During the short flight path, the solvent “flashes off” from the chargeddroplets. This fast evaporation creates a situation in which the chargeddroplets shrink in size but increase in charge density. At a criticallimit, the droplets will break up into yet smaller droplets. Anessentially monodisperse population of fine droplets is ultimatelyproduced. The size of the droplets can range from sub-micron to severalmicrons.

The essentially complete evaporation of solvent from the chargeddroplets results in the formation of relatively uniform particles of thenon-volatile components from the liquid feedstock. The evaporationprocess occurs at a time-scale that does not permit crystallization ofthe non-volatile components. Additionally, evaporative coolingassociated with the extremely rapid solvent evaporation contributes aquenching effect to preserve the particles in an amorphous state.Furthermore, electrospray conditions can be selected and the system canbe configured such that the amorphous particles contain little residualsolvent.

In some embodiments of the disclosure, the liquid feedstock may beformed into an ASD using electrospray techniques and/or devices.Suitable methods and equipment are described, for example, in U.S. Pat.Nos. 6,746,869, 6,764,720, 7,279,322, 7,498,063, 7,951,428, 7,972,661,8,992,603, 9,040,816, 9,050,611, 9,108,217, 9,642,694, 10,562,048, U.S.Patent Publication No. 2014-0158787, U.S. Patent Publication No.2015-0190253, U.S. Patent Publication No. 2016-0038968, U.S. PatentPublication No. 2016-0175881, U.S. Patent Publication No. 2016-0235677,U.S. Patent Publication No. 2019-0193109, and U.S. Patent PublicationNo. 2020-0179963.

As noted above, by using an electrospray technique, the median diameterof the dasatinib ASD particle distribution may be from 0.1 μm to 10 μm,or from 0.2 μm to 5 μm, or from 0.5 μm to 2 μm. It should further benoted that the dasatinib in electrosprayed amorphous particles isgenerally not considered to be solvated. Even where the liquid feedstockmay have been prepared using a solvate form of dasatinib (such asdasatinib monohydrate), the solvate is understood to flash off with theother solvents, and the electrosprayed amorphous particles comprisenon-solvated dasatinib (such as anhydrous dasatinib).

In some embodiments, the electrospray technique may be performed at roomtemperature. In certain embodiments, no heated air is used. In otherembodiments, the liquid feedstock is held at an elevated temperatureduring the electrospray process.

In some embodiments, the electrospray technique may be performed usingone or more capillary nozzles. In certain embodiments, the electrospraytechnique does not use pneumatic nozzles such as nozzles that rely onkinetic energy; pressure nozzles; rotary nozzles or nozzles that rely oncentrifugal energy; or ultrasonic nozzles such as nozzles that rely onacoustic energy. In some embodiments, the electrospray techniquegenerates a yield of over 85%, or over 90%, or over 95%, or over 98%.

In other embodiments, the liquid feedstock may be formed into an ASDthrough spray drying. Generally speaking, spray drying involves theatomization of a liquid feedstock into very small droplets within a hotdrying gas. The feedstock is pumped or otherwise propelled through anozzle or other atomizing apparatus to form droplets within a dryingchamber. Within the drying chamber, the droplets are exposed to anenvironment of the heated drying gas (usually flowing air or nitrogen),leading to flash drying of the droplets (by evaporative removal ofsolvent) and resultant production of solid particles. The driedparticles are collected, generally at an output port in the dryingchamber.

Various apparatus and methods of spray drying may be employed to form anASD of the disclosure. In the practice of the present disclosure, themedian diameter of the ASD particle distribution achieved by spraydrying may be from 1 μm to 40 μm, or from 2 μm to 25 μm, or from 3 μm to20 μm.

In some embodiments, the process for forming an ASD does not require asecondary drying step, i.e., a drying step that occurs after theparticles are produced. In other embodiments, a secondary drying step isemployed to further remove most or all of the residual solvents. Thesecondary drying step can be done under suitable conditions that allowfor the removal of solvent but do not result in the recrystallization ofthe dasatinib. For example, a secondary drying step can be done below aglass transition temperature. A secondary drying step can also be doneat reduced pressure. A combination of elevated temperature and reducedpressure can also be used for a secondary drying step.

Pharmaceutical Compositions

An aspect of the present disclosure relates to pharmaceuticalcompositions comprising dasatinib ASD. The pharmaceutical compositionsof the present disclosure may be in a dosage form appropriate for oraladministration. In some embodiments, the pharmaceutical compositions maybe in the form of granules, or may be prepared as granules as anintermediate step to forming another oral dosage form, such as tablets,sprinkles, or pellets. In some embodiments, the pharmaceuticalcompositions may be in a solid dosage form for oral administration, suchas a capsule, tablet, sprinkle, or pellet. The pharmaceuticalcomposition may also be in the form of an aqueous or nonaqueoussuspension or solution. Such compositions may be prepared using knownexcipients and known preparation methods.

The compositions may comprise a dasatinib ASD of the present disclosureand one or more pharmaceutically acceptable excipients, such as one ormore solubilizers, one or more buffering agent(s), one or morepH-adjusting agents, one or more surfactants, one or more antioxidants,and/or one or more carriers. Pharmaceutical compositions in the form ofsolid oral dosage forms may also comprise one or more filling agents,one or more binding agents, one or more lubricants, one or moredisintegrants, and/or other conventional excipients such as one or moreglidants, for example.

The pharmaceutical compositions of the present disclosure may beprepared using methods known in the art. For example, the dasatinib ASDand the one or more pharmaceutically acceptable additives may be mixedby simple mixing, or may be mixed with a mixing device continuously,periodically, or a combination thereof. Examples of mixing devices mayinclude, but are not limited to, a magnetic stirrer, shaker, a paddlemixer, homogenizer, and any combination thereof.

Solubilizers that may be used in the pharmaceutical compositions of thepresent disclosure include, but are not limited to, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer (SOLUPLUS),d-α-tocopherol acid polyethylene glycol (PEG) 1000 succinate (TPGS),PEG-40 hydrogenated castor oil (CREMOPHOR RH40), PEG-35 castor oil(CREMOPHOR EL), PEG-40 stearate (MYRJ 540), hard fat (such as GELUCIRE33/01), polyoxylglycerides (such as GELUCIRE 44/14), stearoylpolyoxylglycerides (such as GELUCIRE 50/13), PEG-8 caprylic/capricglycerides (such as LABRASOL) and poloxamers (such as PLURONIC,KOLLIPHOR).

In some embodiments, the pharmaceutical compositions may comprise adasatinib ASD and one or more pharmaceutically acceptable excipients,with the proviso that the pharmaceutically acceptable excipients do notcomprise polyvinyl caprolactam-polyvinyl acetate-polyethylene glycolgraft co-polymer (e.g., SOLUPLUS).

Buffering agents that that may be used in the pharmaceuticalcompositions of the present disclosure include, but are not limited to,triethylamine, meglumine, diethanolamine, ammonium acetate, arginine,lysine, histidine, a phosphate buffer (e.g., sodium phosphate tribasic,sodium phosphate dibasic, sodium phosphate monobasic, or o-phosphoricacid), sodium bicarbonate, a Britton-Robinson buffer, a Tris buffer(containing Tris(hydroxymethyl)-aminomethane), a HEPES buffer(containing N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid),acetate, a citrate buffer (e.g., citric acid, citric acid anhydrous,citrate monobasic, citrate dibasic, citrate tribasic, citrate salt),ascorbate, glycine, glutamate, lactate, malate, formate, sulfate, andmixtures thereof.

Further, pH-adjusting agents that that may be used in the pharmaceuticalcompositions of the present disclosure include pharmaceuticallyacceptable acids or bases. For example, acids may include, but are notlimited to, one or more inorganic mineral acids such as hydrochloric,hydrobromic, sulfuric, phosphoric, nitric, and the like; or one or moreorganic acids such as acetic, succinic, tartaric, ascorbic, citric,glutamic, benzoic, methanesulfonic, ethanesulfonic, trifluoroacetic, andthe like. The bases may be one or more inorganic bases or organic bases,including, but not limited to, alkaline carbonate, alkaline bicarbonate,alkaline earth metal carbonate, alkaline hydroxide, alkaline earth metalhydroxide, or amine. For example, the inorganic or organic base may bean alkaline hydroxide such as lithium hydroxide, potassium hydroxide,cesium hydroxide, sodium hydroxide, or the like; an alkaline carbonatesuch as calcium carbonate, sodium carbonate, or the like; or an alkalinebicarbonate such as sodium bicarbonate, or the like; the organic basemay also be sodium acetate.

Surfactants that that may be used in the pharmaceutical compositions ofthe present disclosure may include, but are not limited to, sodiumlauryl sulfate, docusate sodium, dioctyl sodium sulfosuccinate, dioctylsodium sulfonate, benzalkonium chloride, benzethonium chloride,lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenatedcastor oil (e.g., polyoxyethylene hydrogenated castor oil 10, 50, or60), glycerol monostearate, polysorbate (e.g., polysorbate 40, 60, 65,or 80), sucrose fatty acid ester, methyl cellulose, polyalcohols andethoxylated polyalcohols, thiols (e.g., mercaptans) and derivatives,poloxamers, polyethylene glycol-fatty acid esters (e.g., KOLLIPHOR RH40,KOLLIPHOR EL), lecithins, and mixtures thereof.

Antioxidants that that may be used in the pharmaceutical compositions ofthe present disclosure include, but are not limited to, acetylcysteine,ascorbyl palmitate, BHA, BHT, monothioglycerol, potassium nitrate,sodium ascorbate, sodium formaldehyde sulfoxylate, sodium metabisulfite,sodium bisulfate, vitamin E or a derivative thereof, propyl gallate,EDTA (e.g., disodium edetate), DTPA, bismuth sodium triglycollamate, ora combination thereof. Antioxidants may also comprise amino acids suchas methionine, histidine, cysteine and those carrying a charged sidechain, such as arginine, lysine, aspartic acid, and glutamic acid. Anystereoisomer (e.g., l-, d-, or a combination thereof) of any particularamino acid (e.g., methionine, histidine, arginine, lysine, isoleucine,aspartic acid, tryptophan, threonine and combinations thereof) orcombinations of these stereoisomers, may be present so long as the aminoacid is present either in its free base form or its salt form.

Carriers that that may be used in the pharmaceutical compositions of thepresent disclosure include, but are not limited to, water, saltsolutions (e.g., Ringer's solution and the like), alcohols, oils,gelatins, and carbohydrates such as lactose, amylose or starch, fattyacid esters, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinyl pyrrolidine, and mixtures or solutions includingany of the foregoing. The carrier may be used in combination with abuffering agent.

In some embodiments, the composition of the present disclosure maycomprise a carrier at a pH of 5 to 9, or 6 to 8. In certain embodiments,the composition may comprise a carrier having a neutral pH. In certainembodiments, the pH of the carrier may be at or near physiological pH.

In some embodiments, the pharmaceutical compositions of the presentdisclosure may include other suitable pharmaceutical additives suchtonicity-adjusting agents, preservatives, emulsifiers, sweeteners,flavoring agents, suspending agents, thickening agents, colors,viscosity regulators, stabilizers, and osmo-regulators.

Pharmaceutical compositions in solid form may comprise one or morefilling agents, one or more binding agents, one or more lubricants, oneor more disintegrants, and/or other conventional excipients such as oneor more glidants, for example.

Suitable filling agents include acacia, calcium carbonate, calciumsulfate, calcium sulfate dihydrate, compressible sugar, dibasic calciumphosphate anhydrous (e.g., FUJICALIN, EMCOMPRESS), dibasic calciumphosphate dihydrate, tribasic calcium phosphate, monobasic sodiumphosphate, dibasic sodium phosphate, lactose monohydrate, lactoseanhydrous, magnesium oxide, magnesium carbonate, silicon dioxide,magnesium aluminum silicate, maltodextrin, mannitol, methyl cellulose,microcrystalline cellulose (e.g., AVICEL PH-101, AVICEL PH-102),powdered cellulose, starches, sorbitol, dextrose, dextrates, dextrin,sucrose, xylitol and mixtures thereof.

Suitable binding agents include various celluloses and cross-linkedpolyvinylpyrrolidone, microcrystalline cellulose (e.g., AVICEL PH-101,AVICEL PH-102, AVICEL PH-105), or silicified microcrystalline cellulose(e.g., PROSOLV SMCC), for example.

One or more lubricants may be included to reduce friction with andadherence to processing equipment during processing. Examples ofsuitable lubricants include, but are not limited to, magnesium stearate,calcium stearate, zinc stearate, stearic acid, stearyl alcohol, glycerylmonostearate, sodium stearyl fumarate, talc, glyceryl behenate, sodiumbenzoate, sodium lauryl sulfate, and the like. When included, the one ormore lubricant is generally present in the range of 0.1% to 5%, byweight of the pharmaceutical composition. In some embodiments, the oneor more lubricant is generally present in the range of 0.25% to 2%, byweight of the pharmaceutical composition. In certain embodiments, thelubricant is magnesium stearate.

Suitable disintegrants in the practice of the disclosure includenatural, modified or pre-gelatinized starch, sodium starch glycolate,sodium carboxymethyl cellulose, calcium carboxymethyl cellulose,croscarmellose sodium, crospovidone, polyvinylpolypyrrolidone, andmixtures thereof.

Glidants are employed to improve flow properties of a powder or granulemixture prior to further processing (such as tablet compression, forexample). Suitable glidants that may be employed in the compositions ofthe present disclosure include, but are not limited to, colloidal silica(e.g., hydrophobic colloidal silica, such as AEROSIL), silica gel,precipitated silica, and the like. When included, the one or moreglidant is generally present in the range of 0.1% to 5%, by weight ofthe pharmaceutical composition. In some embodiments, the one or moreglidant is generally present in the range of 0.25% to 2%, by weight ofthe pharmaceutical composition.

In some cases, a single excipient may provide more than one function.For example, microcrystalline cellulose (when present) can function asboth a filling agent and a binding agent. Alternatively, suchmulti-functional excipients can be used in combination with otherfunctional excipients. (For example, microcrystalline cellulose may beused with other filling agents and/or other binding agents.)

In some embodiments, the pharmaceutical compositions may be in the formof granules, or may be prepared as granules as an intermediate step toforming another oral dosage form, such as a tablet or pellet, or as afill for a capsule. In some embodiments, granules may comprise one ormore of the pharmaceutically acceptable excipients described above. Incertain embodiments, the granules may comprise the ASD in an amount of20%-70% by weight of the granule; one or more filling agents in anamount of 20% to 70% by weight of the granule; one or more disintegrantsin an amount of 2%-10% by weight of the granule; and one or morelubricants in an amount of 0.2%-5% by weight of the granule. Inparticular embodiments, the granules may comprise the components as setforth in Table 1.

TABLE 1 Components of an exemplary granule formulation in accordancewith particular embodiments of the disclosure. Component % By Weight ofthe Granule Dasatinib ASD  30-70% Dibasic Calcium Phosphate  20-50%Microcrystalline Cellulose   5-20% Croscarmellose Sodium   2-10%Hydrophobic Colloidal Silica 0.2-5% (optional) Magnesium stearate 0.2-5%(optional)

In some embodiments, the pharmaceutical compositions are in the form ofa tablet. In certain embodiments, the tablet may comprise the ASD in anamount of 20%-60% by weight of the tablet; one or more filling agents inan amount of 40%-80% by weight of the tablet; one or more disintegrantsin an amount of 1%-10% by weight of the tablet; and one or morelubricants in an amount of 0.25%-5% by weight of the tablet.

In particular embodiments, the amount of granule in the tablet maydepend on the dasatinib drug load of the ASD that is used to prepare thegranules. In other words, a greater amount of drug load in the ASDresults in a greater amount of dasatinib in the granules, and thereforea smaller amount of granules is needed for the tablets. By way ofexamples only, Tables 2 and 3 list components of exemplary tabletformulations comprising granules that have ASD at drug loads of 60% and80%, respectively.

TABLE 2 Components of an exemplary tablet formulation comprisinggranules of dasatinib ASD particles (60% drug load) in accordance withparticular embodiments of the disclosure. % By Weight of the ComponentTablet Granules Comprising Dasatinib ASD 50-90% (60% drug load) OtherExcipients Microcrystalline Cellulose 5-40% 10-50% in the TabletCroscarmellose Sodium 1-10% Hydrophobic Colloidal Silica 0.5% Magnesiumstearate 0.5%

TABLE 3 Components of an exemplary tablet formulation comprisinggranules of dasatinib ASD particles (80% drug load) in accordance withparticular embodiments of the disclosure. % By Weight of the ComponentTablet Granules Comprising Dasatinib ASD 40-80% (80% drug load) OtherExcipients Microcrystalline Cellulose 10-50% 20-60% in the TabletCroscarmellose Sodium  1-10% Hydrophobic Colloidal Silica 0.5% Magnesiumstearate 0.5%

Pharmaceutical compositions of the disclosure in the form of a tabletmay be prepared using methods known in the art. For example, thedasatinib ASD and the one or more pharmaceutically acceptable additivesmay be blended to provide a tableting blend by hand or bag blending, orusing a suitable device. Examples of suitable blending devices mayinclude, but are not limited to, a tumble blender, v-blender, acousticblender, paddle mixer, screw mixer, and the like.

Suitable tableting blends may then be compressed into tablets weighingfrom 100 to 1000 mg using, for example, a manual tablet press or aconventional mechanical tablet press. Compression force is selected toachieve desired mechanical properties of the tablet without compromisingperformance.

In some embodiments, it may be desirable to form granules as anintermediate step to forming a tableting blend. Granules typically haveimproved flow, handling, blending, and compression properties relativeto ungranulated materials. The granules may be prepared from the ASDparticles by processes known in the art, including wet granulation anddry granulation. In some embodiments, a granule blend is formed bydry-blending granule components, and then the granule blend is densifiedusing a roller compactor which typically forms ribbons of material. Theribbons are then reduced in size by milling to form granules.

Wet granulation techniques may also be employed to form granules,provided the solvents and process selected do not alter the propertiesof the ASD. Improved wetting, disintegrating, dispersing and dissolutionproperties may be obtained by the inclusion of suitable excipients, asdescribed above.

The granule blend (and accordingly the resulting granules) can includesome or all of the components of the tablet. In some embodiments, thegranules may comprise one of more of the pharmaceutically acceptableexcipients described above. After granulation, the granules can beincluded into a tableting blend and compressed into tablets, asdescribed above.

The pharmaceutical compositions of the present disclosure maydemonstrate a desirable level of physical and/or chemical stability oversome suitable period of time, and optionally under acceleratedconditions. The stability of the pharmaceutical compositions can beassessed by different measures. For instance, the pharmaceuticalcompositions may demonstrate chemical stability by having a particularassay value or a particular level of total related substances (e.g.,impurities), measured after storage under accelerated conditions over aspecified period of time. In some embodiments, the pharmaceuticalcompositions may be amorphous as assessed using XRD (i.e., nocrystalline character detected) after storage under the specifiedconditions.

In some embodiments, the pharmaceutical compositions may be essentiallyamorphous as assessed using XRD, after storage under the specifiedconditions. The storage conditions may be one or more of 25° C./60% RH,or 30° C./65% RH, or 40° C./75% RH. The period of time may be one ormore of 1 week, or 2 weeks, or 1 month, or 2 months, or 3 months, or 4months, or 6 months, or 9 months, or 12 months, or 15 months, or 18months, or 21 months, or 2 years, or any period of time therebetween.

In some embodiments, pharmaceutical compositions of the presentdisclosure are “gastric acid-insensitive compositions,” as furtherdescribed below. In some embodiments, pharmaceutical compositions of thepresent disclosure are “improved variability compositions,” as furtherdescribed below.

Treatment of Proliferative Disorders

Aspects of the present disclosure relate to uses of the dasatinib ASDsof the present disclosure, or pharmaceutical compositions comprising theASDs. In the practice of such embodiments of the present disclosure,dasatinib ASDs and pharmaceutical compositions may be suitablyadministered to subjects or to patients.

In some embodiments, the dasatinib ASD or pharmaceutical composition isadministered to a subject. The subject in the methods of the presentdisclosure may be a mammal, which includes, but is not limited to, ahuman, monkey, cow, hog, sheep, horse, dog, cat, rabbit, rat, and mouse.In certain embodiments, the subject is a human. As used herein, thephrase “healthy human subject” means a human that is generally healthyand is not being treated for the disease or condition for which thepharmaceutically active component (e.g., dasatinib) is generally usedfor therapy. Selection of suitable healthy human subjects forpharmacokinetic assessment is within the expertise of one skilled in theart of clinical trial design.

In other embodiments, the dasatinib ASD or pharmaceutical composition isadministered to a human patient. The human patient may be adult or of apediatric age, e.g., younger than 17 years old. In certain embodiments,the human patient is 1 year of age or older. As used herein, a “patient”is a subject, particularly a human, who is being treated for a diseaseor condition for which the pharmaceutically active component (e.g.,dasatinib) is generally used for therapy.

An aspect of the present disclosure relates to the use of the dasatinibASDs of the present disclosure or pharmaceutical compositions of thepresent disclosure to treat a proliferative disorder. Some embodimentsrelate to a method of treating a proliferative disorder, the methodcomprising administering an ASD of the present disclosure, or apharmaceutical composition of the present disclosure, to a patient inneed thereof. Some embodiments relate to a use of a dasatinib ASD or apharmaceutical composition of the present disclosure for treating aproliferative disorder in a patient in need thereof, the use comprisingadministering the dasatinib ASD or pharmaceutical composition to thepatient. Some embodiments relate to a dasatinib ASD or a pharmaceuticalcomposition of the present disclosure for use in treating aproliferative disorder in a patient in need thereof, the use comprisingadministering the dasatinib ASD or the pharmaceutical composition to thepatient. Some embodiments relate to a use of a dasatinib ASD orpharmaceutical composition of the present disclosure in the manufactureof a medicament for treating a proliferative disorder.

In one aspect, the present disclosure relates to a method of treating aproliferative disorder in a patient in need thereof, the methodcomprising administering a therapeutically effective amount of an ASD ofthe present disclosure or of a pharmaceutical composition of the presentdisclosure to the patient.

The proliferative disorder may be cancer. Examples of such proliferativedisorders may include, but are not limited to, leukemias such as acutelymphocytic leukemia (or acute lymphoblastic leukemia), acute myeloidleukemia (or acute myelogenous leukemia), chronic lymphocytic leukemia(or chronic lymphoblastic leukemia), chronic myeloid leukemia (orchronic myelogenous leukemia); age-related macular degeneration anddiabetic retinopathy, anal and oral cancers, angiosarcoma, basal cellcarcinoma and squamous cell carcinoma, bladder cancer, brain cancer,breast cancer, cancer of the central nervous system, cervical, cervixuteri cancer, choriocarcinoma, colon cancer, gastrointestinal stromaltumor, corpus uteri cancer, esophageal cancer, Ewing's Sarcoma, eye orocular cancer, head and neck cancer, hemangioendothelioma, hemangiomasand lymphangiogenesis, Kaposi's Sarcoma, larynx cancer, liver cancer,lung cancer, lymphoma, mouth/pharynx cancer, multiple myeloma; cardiachypertrophy, neuroblastoma, neurofibromatosis, ovary cancer, pancreaticcancer, prostate cancer, rectal cancer, renal cancer, rhabdomyosarcoma,skin melanoma, small cell lung cancer, stomach cancer, testis cancer,throat cancer, tuberous sclerosis, and Wilms Tumor.

In certain embodiments, the proliferative disorder may be Philadelphiachromosome-positive (“Ph+”) chronic myeloid leukemia (“CML”) in chronicphase. In certain embodiments, the proliferative disorder may bechronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML withresistance or intolerance to prior therapy including imatinib. Incertain embodiments, the proliferative disorder may be Ph+ acutelymphoblastic leukemia (“ALL”) with resistance or intolerance to priortherapy. In some embodiments, the proliferative disorder may be Ph+ ALL,and dasatinib may be administered in combination with chemotherapy.

In the methods and uses of the present disclosure, a therapeuticallyeffective amount of the dasatinib ASD or the pharmaceutical compositionof the present disclosure will be based on, among other factors, theroute of administration, the age and size of the patient, and theproliferative disorder being treated. As used herein, the term“therapeutically effective amount” means that amount that is expected toelicit the biological or medical response that is being sought by aclinician.

In some embodiments, a therapeutically effective amount may be 0.01 to10 mg/kg/day, or 0.05 to 7 mg/kg/day of dasatinib. In other embodiments,a therapeutically effective amount may be fixed dose. For instance, thefixed dose may be 5 mg to 400 mg, or 10 mg to 300 mg, or 10 mg to 200mg, per day of dasatinib. In certain embodiments, the fixed dose may be10 mg, or 20 mg, or 25 mg, or 30 mg, or 40 mg, or 50 mg, or 60 mg, or 70mg, or 75 mg, or 80 mg, or 90 mg, or 100 mg, or 110 mg, or 120 mg, or125 mg, or 130 mg, or 140 mg, or 150 mg, or 160 mg, or 170 mg, or 175mg, or 180 mg, or 190 mg, or 200 mg, per day of dasatinib. Depending onthe treatment regimen, the quantity of dasatinib dosed per day may bedosed all at once (once-daily dosing), or may be divided and dosed morefrequently (such as twice-per-day dosing).

As described further below, pharmaceutical compositions of the presentdisclosure may provide enhanced or otherwise desirable bioavailabilityunder a variety of administration conditions. The term “bioavailability”refers to the rate and extent to which an active ingredient is absorbedfrom a pharmaceutical composition and becomes available at the site ofaction. In the case of orally administered pharmaceuticals,bioavailability is generally assessed by monitoring a subject's bloodplasma over time for the presence of an active ingredient (or suitablesurrogate, such as a metabolite) after administration of apharmaceutical composition, to evaluate the pharmacokinetic profile.

From the pharmacokinetic profile, certain relevant pharmacokineticparameters can be established. Such pharmacokinetic parameters caninclude C_(max), T_(max), and/or AUC, for example. C_(max) indicates themaximum observed plasma concentration over the observed time period.T_(max) indicates the time point at which the maximum plasmaconcentration is observed.

AUC indicates the numerical area-under-the-curve (“AUC”) for theconcentration-time curve, and can be assessed for a specified timeinterval 0-t, denoted as AUC_(0-t) (alternatively denoted as AUC_(t)).AUC_(0-t) is generally obtained by numerical integration of theconcentration-time curve over the period t=0 to the time “t” (e.g.,AUC_(0-24 h) or AUC_(24 h) indicates the integral over the time periodfrom t=0 to t=24 hours). AUC_(0-last) (alternatively denoted asAUC_(last)) indicates the integral from t=0 to the last time pointsampled in the observed time period. AUC_(0-inf) (alternatively denotedas AUC_(inf)) indicates the integral from t=0 to t=“infinity,” which isdetermined by extrapolation of obtained data using commonly employedpharmacokinetic statistical modeling techniques.

Typically, plasma concentration data is log-transformed for analysis.For most pharmacokinetic analyses, data for a number of test subjects ispooled for analysis. When data is pooled, the relevant pharmacokineticparameters may be expressed as a population geometric mean, inaccordance with conventional pharmacokinetic statistical analyses andmethods.

Administration of an ASD or pharmaceutical composition of the presentdisclosure can be characterized by the pharmacokinetic profile, or bythe observed or calculated pharmacokinetic parameters resulting from theadministration of the ASD or pharmaceutical composition at certaindosages to a subject or patient, under stated administration conditions.

By way of example only (and as further described below), administrationof the ASD or pharmaceutical composition of the present disclosure undera fasted state or fasted conditions can be characterized by thepharmacokinetic profile resulting from the administration, or byobserved pharmacokinetic parameters.

The phrase “fasted state” or “fasting conditions”, as used herein forhuman subjects, refers to a subject being at least 2 hours, moresuitably at least 4 hours, or more suitably at least 8 hours after thesubject's previous meal. Preferably, the fasted state or fastingconditions follows an overnight fast of at least 10 hours. Similarly,“fasted state” or fasting conditions”, as used herein, refers to thecondition in which the subject has not eaten for at least two hours,more suitably at least 4 hours, or more suitably at least 8 hours; orthe condition of the subject following an overnight fast of at least 10hours. Moreover, the fasted state or fasting conditions may also requirecontinued fasting for at least 1 hour, more suitably at least 2 hours,or more suitably at least 4 hours after the administration.

Likewise, reference to administration in a “fed state” or under “fedconditions” to a human subject, as used herein, refers to administrationto the subject from 30 minutes after the subject starts ingesting a mealto 1 hour after complete ingestion of a meal. Similarly, “fed state” or“fed conditions” refers to the condition of a subject 30 minutes afterthe subject starts ingesting a meal to 1 hour after complete ingestionof a meal.

Methods of Co-Administering with a Gastric Acid-Reducing Agent

In some embodiments, the dasatinib ASD or pharmaceutical compositionaccording to the present disclosure can be co-administered with agastric acid-reducing agent.

“Gastric acid-reducing agent” refers herein to any agent that acts tosignificantly reduce the amount of acid in a subject's or patient'sstomach. Acid reduction can be due to suppression or blocking of acidsecretion, or by neutralization of stomach acid. Examples of gastricacid-reducing agents include, but are not limited to, histamine-2receptor antagonists (or H₂ antagonists) such as famotidine, cimetidine,nizatidine, and ranitidine; proton pump inhibitors (or PPIs) such asrabeprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, anddexlansoprazole; and antacids (which neutralize stomach acidity andthereby elevate gastric pH) such as aluminum hydroxide, magnesiumhydroxide, sodium citrate, sodium carbonate, sodium bicarbonate, calciumcarbonate, magnesium trisilicate, and the like.

The gastric acid-reducing agent may be administered in accordance withthe dosing information that is known in the art for the agent, oraccording to a physician's instructions. A “standard dosage” as usedherein indicates a dosage of the agent within a suitable range for thepatient according to the dosing recommendation from the product'slabeling, or according to the physician's instructions.

As used herein, “co-administration” (or “co-administered”) refers to asituation in which a patient is being treated for two or more conditionssimultaneously, by administration of two or more therapeutic agents. Byway of example only, a patient may be treated for a proliferativedisorder as described herein with dasatinib as a therapeutic agent,while also being treated for another condition, such as acid reflux orulcers, with a second therapeutic agent such as a proton pump inhibitor.Since both therapeutic agents are dosed at least once daily, the twotherapeutic agents are “co-administered,” and consideration must begiven to whether the administration of one of the therapeutic agents mayaffect the absorption or efficacy of the other.

In the context of the present disclosure, the phrase “can beco-administered” means that the two (or more) therapeutic agents ofinterest can be co-administered without a detrimental reduction in theexposure of dasatinib. “Without a detrimental reduction” indicates thatthe realized exposure would be similar to the exposure realized when thegastric acid-reducing agent is not co-administered. Any difference inthe realized exposure would be insubstantial and/or therapeuticallyinconsequential. In contrast, when a detrimental reduction in exposurewould be realized, then co-administration should be avoided. A“detrimental reduction” means a substantial and material reduction inthe realized exposure. By way of example, if the realized exposure wouldbe less than or equal to a level recognized as a sub-therapeuticexposure, then the co-administration would result in a detrimentalreduction in exposure.

“Therapeutically relevant exposure” as used herein means an exposurethat is comparable to the exposure that would be expected for aconventional commercially available immediate release formulation ofdasatinib of corresponding strength, dosed according to its labeledinstructions. By “comparable,” it is meant that administration of theASD or the pharmaceutical composition of the disclosure to the subjectmay provide AUC_(0-t) (such as AUC_(0-24 h), AUC_(last) or AUC_(0-inf))and C_(max), in the subject's plasma that produce a similar therapeuticeffect. By way of example only, one way to determine a similartherapeutic effect is if the AUC_(0-t) or C_(max) is within the 80% to125% bioequivalence criteria compared to administration of theconventional commercially available immediate release composition to thesame subject, dosed according to its labeled instructions.

As used herein, the phrase “gastric acid-insensitive composition”indicates a pharmaceutical composition of the present disclosure thatcan be administered without regard to the patient or subject's gastricpH. A gastric acid-insensitive composition provides a therapeuticallyrelevant exposure to the patient or subject across a range of gastric pHvalues. Accordingly, a gastric acid-insensitive composition can beadministered whether or not the patient or subject has ingested agastric acid-reducing agent, or whether or not the patient has acondition that causes elevated gastric pH (as further discussed below).

Embodiments of the disclosure relate to administering a gastricacid-reducing agent shortly before, concurrently with, or shortly afterthe dasatinib ASD or pharmaceutical composition of the disclosure. Theterm “shortly before” as used herein means that a gastric acid-reducingagent was administered to the subject 4 hours or less, or 3 hours orless, or 2 hours or less, or 1 hour or less, or 45 minutes or less, or30 minutes or less, or 15 minutes or less, prior to the administrationof the dasatinib ASD or pharmaceutical composition. The term“concurrently” or “concomitantly” as used herein means that a gastricacid-reducing agent was administered to the subject within 30 minutes orless, or within 20 minutes or less, or within 15 minutes or less, orwithin 10 minutes or less, or within 5 minutes or less, or within 4minutes or less, or within 3 minutes or less, or within 2 minutes orless, or within 1 minute or less, or simultaneously, of theadministration of the dasatinib ASD or pharmaceutical composition. Theterm “shortly after” as used herein means that a gastric acid-reducingagent was administered to the subject 4 hours or less, or 3 hours orless, or 2 hours or less, or 1 hour or less, or 45 minutes or less, or30 minutes or less, or 15 minutes or less, after the administration ofthe dasatinib ASD or pharmaceutical composition.

In some embodiments, administration of an ASD or pharmaceuticalcomposition of the present disclosure to a subject who was concurrentlyadministered a gastric acid-reducing agent exhibits a pharmacokineticprofile of dasatinib that is similar to the pharmacokinetic profileresulting from administration of the ASD or pharmaceutical compositionto a subject who was not concurrently administered a gastricacid-reducing agent. In certain embodiments, single administration tothe subject of the ASD or pharmaceutical composition concurrently with agastric-acid reducing agent results in an AUC of dasatinib that iswithin 50%, or within 40%, or within 30%, of the AUC of dasatinib thatresults from administration of the ASD without concurrent administrationof the gastric acid-reducing agent. In certain embodiments, the AUC isAUC_(0-24 h). In other embodiments, the AUC is AUC_(0-inf).

In some embodiments, single administration of an ASD or pharmaceuticalcomposition of the present disclosure to a subject or patient who wasconcurrently, shortly before, or shortly after administered a gastricacid-reducing agent exhibits greater AUC and/or C_(max) as compared tosingle administration of the standard commercial, immediate-releasecomposition of dasatinib (e.g., SPRYCEL) to a subject or patient who wasconcurrently, shortly before, or shortly after administered a gastricacid-reducing agent. In certain embodiments, single administration ofthe ASD or pharmaceutical composition to a subject who was concurrently,shortly before, or shortly after administered a gastric-acid reducingagent results in an AUC and/or C_(max) of dasatinib that is at least 80%greater, or at least 100% greater, or at least 150% greater, or at least200% greater, than the AUC and/or C_(max) of dasatinib that results fromadministration of the standard commercial, immediate-release compositionof dasatinib concurrently, shortly before, or shortly after thegastric-acid reducing agent, where the ASD or pharmaceutical compositioncontains the same dosage as the standard commercial, immediate-releasecomposition of dasatinib. In certain embodiments, the AUC isAUC_(0-24 h). In other embodiments, the AUC is AUC_(0-inf).

In some embodiments, single administration of an ASD or pharmaceuticalcomposition of the present disclosure to a subject or patient who wasconcurrently administered a gastric acid-reducing agent exhibits greaterAUC and/or C_(max) as compared to single administration of the standardcommercial, immediate-release composition of dasatinib (e.g., SPRYCEL)to a subject or patient who was concurrently administered a gastricacid-reducing agent. In certain embodiments, single administration tothe subject or patient of the amorphous solid dispersion orpharmaceutical composition concurrently with a gastric-acid reducingagent results in an AUC and/or C_(max) of dasatinib that is at least 80%greater, or at least 100% greater, or at least 150% greater, or at least200% greater, than the AUC and/or C_(max) of dasatinib that results fromadministration of the standard commercial, immediate-release compositionof dasatinib concurrently with the gastric-acid reducing agent, wherethe amorphous solid dispersion or pharmaceutical composition containsthe same dosage as the standard commercial, immediate-releasecomposition of dasatinib. In certain embodiments, the AUC isAUC_(0-24 h). In other embodiments, the AUC is AUC_(0-inf).

In some embodiments, the dasatinib ASD or pharmaceutical composition ofthe present disclosure may be administered without regard to whether thesubject is administered a gastric acid-reducing agent. Thus, the subjectmay be administered the dasatinib ASD or pharmaceutical composition nomatter whether the subject was administered a gastric acid-reducingagent shortly before the dasatinib ASD or pharmaceutical composition; isbeing administered a gastric acid-reducing agent concurrently or shortlyafter the administration of the dasatinib ASD or pharmaceuticalcomposition, or is not being administered a gastric acid-reducing agentat all.

Some embodiments relate to a method of delivering dasatinib to a subjectwithout regard to whether the subject is administered a gastricacid-reducing agent, the method comprising administering the ASD orpharmaceutical composition of the disclosure to the subject. Someembodiments relate to a use of a dasatinib ASD or pharmaceuticalcomposition of the present disclosure for delivering dasatinib to asubject without regard to whether the subject is administered a gastricacid-reducing agent, the use comprising administering the ASD orpharmaceutical composition to the subject. Some embodiments relate to adasatinib ASD or pharmaceutical composition of the present disclosurefor use in delivering dasatinib to a subject without regard to whetherthe subject is administered a gastric acid-reducing agent, the usecomprising administering the ASD or pharmaceutical composition to thesubject. Some embodiments relate to a use of a dasatinib ASD orpharmaceutical composition of the present disclosure in the manufactureof a medicament for delivering dasatinib to a subject without regard towhether the subject is administered a gastric acid-reducing agent, thedelivery comprising administering the ASD or pharmaceutical compositionto the subject. According to these embodiments, the subject may beadministered the dasatinib ASD or pharmaceutical composition no matterwhether the subject was administered a gastric acid-reducing agentshortly before the dasatinib ASD or pharmaceutical composition; is beingadministered a gastric acid-reducing agent concurrently or shortly afterthe administration of the dasatinib ASD or pharmaceutical composition;or is not being administered a gastric acid-reducing agent at all.

Embodiments of the disclosure relate to treatment regimens for treatinga proliferative disorder in a patient in need thereof. In someembodiments, the regimen may comprise (a) administering to the patient afirst dose, the first dose comprising a standard dosage of a proton pumpinhibitor or H₂ antagonist; and (b) within 20 hours after the firstdose, administering a second dose to the patient, the second dosecomprising a therapeutically effective amount of a dasatinib ASD orpharmaceutical composition of the disclosure. In certain embodiments,the second dose is administered within 16 hours, or within 12 hours, orwithin 8 hours, or within 6 hours, or within 4 hours, or within 2 hours,after the first dose. In some embodiments, the regimen may comprise (a)administering to the patient a first dose, the first dose comprising astandard dosage of an antacid; and (b) within 2 hours before the firstdose, administering a second dose to the patient, the second dosecomprising a dasatinib ASD or pharmaceutical composition of the presentdisclosure. In some embodiments, the regimen may comprise (a)administering to the patient a first dose, the first dose comprising astandard dosage of an antacid; and (b) within 2 hours after the firstdose, administering a second dose to the patient, the second dosecomprising a dasatinib ASD or pharmaceutical composition of the presentdisclosure. In some embodiments, the regimen may comprise (a)administering to the patient a first dose, the first dose comprising astandard dosage of an antacid; and (b) within 2 hours before or within 2hours after the first dose, administering a second dose to the patient,the second dose comprising a dasatinib ASD or pharmaceutical compositionof the present disclosure.

Methods of Treating a Patient Having Elevated Gastric pH

The dasatinib ASDs or pharmaceutical compositions of the presentdisclosure may be suitably administered to subjects or patients with anelevated gastric pH. (In contrast, a conventional immediate-releasecomposition of dasatinib would be unsuitable for therapeuticadministration to a patient having elevated gastric pH.)

One aspect of the present disclosure relates to the use of the dasatinibASDs or pharmaceutical compositions of the present disclosure to deliverdasatinib to a subject or patient with elevated gastric pH. Someembodiments relate to a method of delivering dasatinib to a subject withelevated gastric pH, the method comprising administering the ASD orpharmaceutical composition of the present disclosure to the subject orpatient. Some embodiments relate to a use of a dasatinib ASD orpharmaceutical composition of the present disclosure for deliveringdasatinib to a subject or patient with elevated gastric pH, the usecomprising administering the ASD or pharmaceutical composition to thesubject or patient. Some embodiments relate to a dasatinib ASD orpharmaceutical composition of the present disclosure for use indelivering dasatinib to a subject or patient with elevated gastric pH,the use comprising administering the ASD or pharmaceutical compositionto the subject or patient. Some embodiments relate to a use of adasatinib ASD or pharmaceutical composition of the present disclosure inthe manufacture of a medicament for delivering dasatinib to a subject orpatient with elevated gastric pH, the delivery comprising administeringthe ASD or pharmaceutical composition to the subject or patient.

As used herein, “gastric pH” refers to the pH inside a subject's orpatient's stomach. Gastric pH may be considered as “elevated” when it isgreater than 3.5, or greater than 4, or greater than 5, measured underfasting conditions. Gastric pH can be evaluated using standard methods,or an elevated gastric pH can be inferred from the known effects of, forexample, treatment with gastric acid-reducing agents or an identifiedcondition that regularly leads to a measurable elevated gastric pH.

In the practice of the present disclosure, subject or patient may havean elevated gastric pH due to different reasons, including, but notlimited to, the subject or patient was administered a gastricacid-reducing agent, or the subject or patient may have a condition thatleads to elevated gastric pH. Elevated gastric pH can result fromconditions such as hypochlorhydria or achlorhydria, or infection byHelicobacter pylori (H. pylori) bacteria, for example.

As used herein, the phrase “chronically elevated” in reference togastric pH means that the subject or patient experiences elevatedgastric pH on a persistent or recurring basis. Chronically elevatedgastric pH can result from, for example, conditions such ashypochlorhydria or achlorhydria, or infection by Helicobacter pyloribacteria. In particular, a conventional immediate-release composition ofdasatinib would be unsuitable for therapeutic administration to asubject or patient having chronically elevated gastric pH, due to thelikelihood of a detrimental reduction in the resulting exposure todasatinib.

In some embodiments, the methods of the disclosure may contain a step ofidentifying a condition by which the patient's gastric pH is elevated(including conditions by which it is chronically elevated). Such a stepmay comprise diagnosing the underlying cause of the elevated gastric pH.It is known in medical practice how to diagnose hypochlorhydria orachlorhydria in patient, or how to test for a Helicobacter pyloribacteria infection. Hypochlorhydria or achlorhydria can be diagnosed,for example, by measuring stomach acid levels under differentconditions. Helicobacter pylori bacterial infection can be diagnosed byan appropriate blood test, stool test, breath test, or scope test, forexample.

In some embodiments, the dasatinib ASD or pharmaceutical composition maybe administered to a subject or patient without regard to gastric pH.Thus, the subject or patient may be administered the dasatinib ASD orpharmaceutical composition no matter whether the subject or patient hasnormal gastric pH (i.e., gastric pH below 3.5, generally in the range1.5 to 3) or has elevated gastric pH as described herein. This isbeneficial when, for example, the subject or patient has gastric pH thatfluctuates due to irregular or episodic use of gastric acid-reducingagents, or if the subject or patient has hypochlorhydria (resulting in agastric pH that may fluctuate depending on factors such as whether thesubject or patient has recently eaten).

In some embodiments, administration of an ASD or pharmaceuticalcomposition of the present disclosure to a subject or patient who haselevated gastric pH exhibits a pharmacokinetic profile for dasatinibthat is similar to the pharmacokinetic profile resulting fromadministration of the ASD or pharmaceutical composition to a subject orpatient who has normal gastric pH. In certain embodiments, singleadministration of the ASD or pharmaceutical composition to a subject orpatient with elevated gastric pH results in AUC_(0-t) (such asAUC_(0-24 h), AUC_(last) or AUC_(0-inf)) and/or C_(max) of dasatinibthat is within 50%, or within 40%, or within 30%, of the AUC_(0-t)and/or C_(max) of dasatinib that results from single administration ofthe ASD or pharmaceutical composition to a subject or patient withnormal gastric pH. In certain embodiments, the AUC_(0-t) isAUC_(0-24 h). In other embodiments, the AUC_(0-t) is AUC_(0-inf).

In certain embodiments, administration of the ASD or pharmaceuticalcomposition of the present disclosure in a subject or patient withelevated gastric pH may provide AUC_(0-t) (such as AUC_(0-24 h),AUC_(last) or AUC_(0-inf)) and C_(max) in the subject's or patient'splasma that are within the 80% to 125% bioequivalence criteria comparedto administration of the conventional commercially availableimmediate-release composition dosed to subjects or patients with normalgastric pH. In certain embodiments, the AUC_(0-t) is AUC_(0-24 h). Inother embodiments, the AUC_(0-t) is AUC_(0-inf).

In the practice of the present disclosure, administration of an ASD or apharmaceutical composition can provide enhanced exposure as compared tostandard immediate-release compositions. In some embodiments, singleadministration of an ASD or pharmaceutical composition of the presentdisclosure to a subject or patient who has elevated gastric pH exhibitsgreater AUC and/or C_(max) as compared to single administration of thestandard commercial, immediate-release composition of dasatinib (e.g.,SPRYCEL) to a subject or patient who has elevated gastric pH. (It shouldbe understood that the same molar quantity or “label claim” of dasatinibis administered in each case.) In certain embodiments, the AUC isAUC_(0-24 h). In other embodiments, the AUC is AUC_(0-inf). In certainembodiments, single administration of the ASD or pharmaceuticalcomposition to a subject or patient with elevated gastric pH results inAUC_(0-t) and/or C_(max) of dasatinib that is at least 80% greater, orat least 100% greater, or at least 150% greater, or at least 200%greater, than the AUC_(0-t) and/or C_(max) of dasatinib that resultsfrom administration of the standard commercial, immediate-releasecomposition of dasatinib to the subject or patient with elevated gastricpH. In certain embodiments, the AUC_(0-t) is AUC_(0-24 h). In otherembodiments, the AUC_(0-t) is AUC_(0-inf).

Further, one aspect of the present disclosure relates to the use of thedasatinib ASDs or pharmaceutical compositions of the present disclosureto deliver dasatinib to a subject without regard to the subject'sgastric pH. Some embodiments relate to a method of delivering dasatinibto a subject without regard to the subject's gastric pH, the methodcomprising administering the ASD or pharmaceutical composition of thepresent disclosure to the subject. Some embodiments relate to a use of adasatinib ASD or pharmaceutical composition of the present disclosurefor delivering dasatinib to a subject without regard to the subject'sgastric pH, the use comprising administering the ASD or pharmaceuticalcomposition to the subject. Some embodiments relate to a dasatinib ASDor pharmaceutical composition of the present disclosure for use indelivering dasatinib to a subject without regard to the subject'sgastric pH, the use comprising administering the ASD or pharmaceuticalcomposition to the subject. Some embodiments relate to a use of adasatinib ASD or pharmaceutical composition of the present disclosure inthe manufacture of a medicament for delivering dasatinib to a subjectwithout regard to the subject's gastric pH, the delivery comprisingadministering the ASD or pharmaceutical composition to the subject.According to these embodiments, the subject may be administered thedasatinib ASD or pharmaceutical composition no matter whether thesubject has normal gastric pH or has elevated gastric pH as describedherein.

Pharmaceutical Composition Having Improved Variability

The pharmaceutical compositions of the present disclosure may, in someembodiments, provide a less variable in vivo pharmacokineticperformance.

As used herein, the phrase “improved variability composition” refers toa composition of the present disclosure that exhibits a lowercoefficient of variation with respect to one or more pharmacokineticparameters when administered to healthy human subjects, as compared tothe coefficient of variation observed for the standard commercial,immediate-release composition of dasatinib (e.g., SPRYCEL) whenadministered under similar conditions.

In some embodiments, the improved variability composition provides acoefficient of variation with respect to at least one pharmacokineticparameter that is 30% lower, 25% lower, 20% lower, 15% lower, or 10%lower than the coefficient of variation observed for the standardcommercial, immediate-release composition of dasatinib (e.g., SPRYCEL)when administered under similar conditions. The pharmacokineticparameter can be any of C_(max), AUC_(last) and AUC_(0-inf). In someembodiments, the improved variability composition provides animprovement with respect to C_(max) and at least one of AUC_(last) andAUC_(0-inf). In other embodiments, the improved variability compositionprovides an improvement with respect to all of C_(max), AUC_(last) andAUC_(0-inf).

In particular, it has been observed that a composition according to thepresent disclosure can provide a lower coefficient of variation forpharmacokinetic parameters when administered to healthy human subjectshaving normal gastric pH and in a fasted state. As shown in Example 8, atest composition exhibited a lower coefficient of variation with respectto C_(max), AUC_(last) and AUC_(0-inf) under these conditions. Theobserved CV for the test composition was at least 30% lower for each ofthese parameters, as compared to the test composition.

Kit Comprising a Pharmaceutical Composition and a Package Insert

In some embodiments, the disclosure provides a kit containing apharmaceutical composition according to any of the above-describedaspects of the disclosure, as well as a package insert. As used herein,a “kit” is a commercial unit of sale, which may comprise a fixed numberof doses of the pharmaceutical composition. By way of example only, akit may provide a 30-day supply of dosage units of one or more fixedstrengths, the kit comprising 30 dosage units, 60 dosage units, 90dosage units, 120 dosage units, or other appropriate number according toa physician's instruction. As another example, a kit may provide a90-day supply of dosage units.

As used herein, “package insert” means a document which providesinformation on the use of the pharmaceutical composition, safetyinformation, and other information required by a regulatory agency. Apackage insert can be a physical printed document in some embodiments.Alternatively, a package insert can be made available electronically tothe user, such as via the Daily Med service of the National Library ofMedicines of the National Institute of Health, which provides up-to-dateprescribing information. (Seehttps://dailymed.nlm.nih.gov/dailymed/index.cfm.)

In some embodiments, the package insert informs a user of the kit thatthe pharmaceutical composition can be co-administered with a gastricacid-reducing agent. In some embodiments, the package insert does notcomprise a warning that the pharmaceutical composition should not beco-administered with H₂ antagonists or proton pump inhibitors.

In some embodiments, the package insert may inform a user of the kitthat an antacid can be co-administered with the pharmaceuticalcomposition. In some embodiments, the package insert may not inform theuser to use an antacid approximately 2 hours before or approximately 2hours after administration of the pharmaceutical composition. In someembodiments, the package insert may inform the user that an antacid canbe used within approximately 2 hours before or within approximately 2hours after administration of the pharmaceutical composition.

In some embodiments, the package insert informs a user of the kit thatthe pharmaceutical composition can be suitably administered to a userhaving chronically elevated gastric pH. In some embodiments, the packageinsert informs a user of the kit that the pharmaceutical composition canbe suitably administered to a patient diagnosed with or afflicted byachlorhydria or hypochlorhydria. In some embodiments, the package insertinforms a user of the kit that the pharmaceutical composition can besuitably administered to a patient diagnosed with or afflicted byHelicobacter pylori infection.

The present disclosure will be further illustrated and/or demonstratedin the following Examples, which are given forillustration/demonstration purposes only and are not intended to limitthe disclosure in any way.

Embodiments of the Disclosure Include

Embodiment ASD1 is an amorphous solid dispersion comprising dasatiniband one or more polymers.

Embodiment ASD2 is an amorphous solid dispersion comprising dasatiniband one or more polymers; wherein the dasatinib and the one or morepolymers are present in the amorphous solid dispersion in a w/w ratio of30:70 to 95:5 (dasatinib:polymer). Embodiment ASD3 is an amorphous soliddispersion comprising dasatinib and one or more polymers, wherein thedasatinib and the one or more polymers are present in the amorphoussolid dispersion in a w/w ratio of 40:60 to 90:10 (dasatinib:polymer).Embodiment ASD4 is an amorphous solid dispersion comprising dasatiniband one or more polymers, wherein the dasatinib and the one or morepolymers are present in the amorphous solid dispersion in a w/w ratio of40:60 to 70:30 (dasatinib:polymer). Embodiment ASDS is an amorphoussolid dispersion comprising dasatinib and one or more polymers, whereinthe dasatinib and the one or more polymers are present in the amorphoussolid dispersion in a w/w ratio of 70:30 to 95:5 (dasatinib:polymer).

Embodiment ASD6 is the amorphous solid dispersion according to any ofEmbodiments ASD1 to ASDS, wherein the one or more polymers exhibitspH-dependent solubility. Embodiment ASD7 is the amorphous soliddispersion according to any of Embodiments ASD1 to ASD6, wherein the oneor more polymers comprises a methacrylic acid and ethyl acrylatecopolymer. Embodiment ASD8 is the amorphous solid dispersion accordingto any of Embodiments ASD1 to ASD7, wherein the one or more polymersconsists essentially of a methacrylic acid and ethyl acrylate copolymer.Embodiment ASD9 is the amorphous solid dispersion according to any ofEmbodiments ASD1 to ASD8, wherein the one or more polymers comprise amethacrylic acid and ethyl acrylate copolymer that is insoluble in anaqueous medium at pH of 5 or lower, and soluble in an aqueous medium atpH 5.5 or greater. Embodiment ASD10 is the amorphous solid dispersionaccording to any of Embodiments ASD1 to ASD9, wherein the one or morepolymers comprises a copolymer of dimethylaminoethyl methacrylate, butylmethacrylate, and methyl methacrylate. Embodiment ASD11 is the amorphoussolid dispersion according to any of Embodiments ASD1 to ASD10, whereinthe one or more polymers consists essentially of a copolymer ofdimethylaminoethyl methacrylate, butyl methacrylate, and methylmethacrylate.

Embodiment ASD12 is the amorphous solid dispersion according to any ofEmbodiments ASD1 to ASD11, wherein the one or more polymers comprises ahydroxypropyl methylcellulose. Embodiment ASD13 is the amorphous soliddispersion according to any of Embodiments ASD1 to ASD12, wherein theone or more polymers consists essentially of a hydroxypropylmethylcellulose. Embodiment ASD14 is the amorphous solid dispersionaccording to any of Embodiments ASD1 to ASD13, wherein the one or morepolymers comprise a hydroxypropyl methylcellulose characterized by amethoxyl substitution of 28 to 30% and a hydroxypropoxyl substitution of7 to 12%. Embodiment ASD15 is the amorphous solid dispersion accordingto any of Embodiments ASD1 to ASD14, wherein the one or more polymerscomprise a hydroxypropyl methylcellulose characterized by a viscosity ofabout 2 to about 18 mPa·s, as determined at 20° C. for a 2% solution inwater. Embodiment ASD16 is the amorphous solid dispersion according toany of Embodiments ASD1 to ASD15, wherein the one or more polymerscomprise a hydroxypropyl methylcellulose characterized by a numberaverage molecular weight (Mn) of about 20 kDa or lower.

Embodiment ASD17 is the amorphous solid dispersion according to any ofEmbodiments ASD1 to ASD16 wherein the amorphous solid dispersionconsists essentially of dasatinib and the one or more polymers.

Embodiment ASD18 is the amorphous solid dispersion according to any ofEmbodiments ASD1 to ASD17, wherein the amorphous solid dispersioncomprises one or more antioxidants. Embodiment ASD19 is the amorphoussolid dispersion according to any of Embodiments ASD1 to ASD18, whereinthe amorphous solid dispersion comprises one or more antioxidants thatare present in an amount of about 0.001% to about 2.0% by weight of theamorphous solid dispersion. Embodiment ASD20 is the amorphous soliddispersion according to any of Embodiments ASD1 to ASD19, wherein theamorphous solid dispersion comprises one or more antioxidants that arepresent in an amount of about 0.05% to about 0.5% by weight of theamorphous solid dispersion. Embodiment ASD21 is the amorphous soliddispersion according to any of Embodiments ASD1 to ASD20, wherein theamorphous solid dispersion comprises one or more antioxidants selectedfrom propyl gallate.

Embodiment ASD22 is the amorphous solid dispersion according to any ofEmbodiments ASD1 to ASD21, wherein the amorphous solid dispersion isprepared by a process comprising electrospraying. Embodiment ASD23 isthe amorphous solid dispersion according to any of Embodiments ASD1 toASD22, wherein the amorphous solid dispersion is an electrosprayedamorphous solid dispersion. Embodiment ASD24 is the amorphous soliddispersion according to any of Embodiments ASD1 to ASD23, wherein theamorphous solid dispersion is prepared by a process comprising spraydrying. Embodiment ASD25 is the amorphous solid dispersion according toany of Embodiments ASD1 to ASD24, wherein the amorphous solid dispersionis a spray-dried amorphous solid dispersion.

Embodiment ASD26 is the amorphous solid dispersion according to any ofEmbodiments ASD1 to ASD25, wherein the amorphous solid dispersionremains amorphous or essentially amorphous as determined by powder X-raydiffraction (XRD) after storage at 40° C./75% relative humidity for 6months. Embodiment ASD27 is the amorphous solid dispersion according toany of Embodiments ASD1 to ASD26, wherein the amorphous solid dispersionremains amorphous or essentially amorphous as determined by powder X-raydiffraction after storage at 25° C./60% relative humidity for 6 months.

Embodiment ASD28 is the amorphous solid dispersion according to any ofEmbodiments ASD1 to ASD27, wherein the amorphous solid dispersioncomprises a water content as measured by coulometric Karl Fischertitration of less than about 8% after storage at 25° C./60% RH for 6months. Embodiment ASD29 is the amorphous solid dispersion according toany of Embodiments ASD1 to ASD28, wherein the amorphous solid dispersioncomprises a water content as measured by coulometric Karl Fischertitration of less than about 8% after storage at 40° C./75% RH for 6months.

Embodiment ASD30 is the amorphous solid dispersion according to any ofEmbodiments ASD1 to ASD29, wherein the amorphous solid dispersion ischaracterized by an assay level of at least 95% as measured by highperformance liquid chromatography (HPLC) after storage at 40° C./75%relative humidity for 6 months. Embodiment ASD31 is the amorphous soliddispersion according to any of Embodiments ASD1 to ASD30, wherein theassay level of the amorphous solid dispersion is at least 97% afterstorage at 40° C./75% relative humidity for 6 months.

Embodiment ASD32 is the amorphous solid dispersion according to any ofEmbodiments ASD1 to ASD31, wherein the amorphous solid dispersioncomprises a total related substances as measured by HPLC of less than1.5% after storage at 25° C./60% RH for 12 months. Embodiment ASD33 isthe amorphous solid dispersion according to any of Embodiments ASD1 toASD32, wherein the amorphous solid dispersion comprises a total relatedsubstances as measured by HPLC of less than 2% after storage at 40°C./75% RH for 6 months.

Embodiment ASD34 is the amorphous solid dispersion according to any ofEmbodiments ASD1 to ASD33, wherein the amorphous solid dispersioncomprises a glass transition temperature as measured by modulateddifferential scanning calorimetry that changes by less than 5° C. afterstorage at 25° C./60% RH for 6 months. Embodiment ASD35 is the amorphoussolid dispersion according to any of Embodiments ASD1 to ASD34, whereinthe amorphous solid dispersion comprises a glass transition temperatureas measured by modulated differential scanning calorimetry that does notchange by more than 10° C. after storage at 40° C./75% RH for 6 months.Embodiment ASD36 is the amorphous solid dispersion according to any ofEmbodiments ASD1 to ASD35, wherein the amorphous solid dispersioncomprises a glass transition temperature as measured by modulateddifferential scanning calorimetry that changes by less than about 6° C.after storage at 40° C./75% RH for up to 6 months.

Embodiment PC1 is a pharmaceutical composition comprising the amorphoussolid dispersion according to any of Embodiments ASD1 to ASD36.Embodiment PC2 is a pharmaceutical composition comprising the amorphoussolid dispersion according to any of Embodiments ASD1 to ASD36, and oneor more pharmaceutically acceptable additives. Embodiment PC3 is thepharmaceutical composition of Embodiment PC2, wherein the one or morepharmaceutically acceptable additives comprises one or moresolubilizers, one or more buffering agent, one or more pH-adjustingagents, one or more surfactants, one or more antioxidants, one or morecarriers, or a combination thereof. Embodiment PC4 is the pharmaceuticalcomposition of Embodiment PC2, wherein the one or more pharmaceuticallyacceptable additives comprises one or more filling agents, one or morebinding agents, one or more lubricants, one or more disintegrants, oneor more glidants, or a combination thereof. Embodiment PC5 is thepharmaceutical composition of Embodiment PC4, wherein the pharmaceuticalcomposition is a solid dosage form suitable for oral administration.

Embodiment PC6 is the pharmaceutical composition of Embodiment PC1 toPC5, wherein the pharmaceutical composition is a gastricacid-insensitive composition.

Embodiment PC7 is the pharmaceutical composition of Embodiment PC1 toPC6, wherein the pharmaceutical composition is an improved variabilitycomposition.

Embodiment MT1 is a method of treating a proliferative disorder in apatient in need thereof, the method comprising administering to thepatient a pharmaceutical composition according to any of Embodiments PC1to PC7.

Embodiment MT2 is a method of treating a proliferative disorder in apatient in need thereof, the method comprising administering to thepatient a pharmaceutical composition according to any of Embodiments PC1to PC7, wherein the pharmaceutical composition is administered withoutregard to whether the patient is co-administered a gastric acid-reducingagent.

Embodiment MT3 is a method of treating a proliferative disorder in apatient in need thereof, the method comprising administering to thepatient a pharmaceutical composition according to any of Embodiments PC1to PC7, wherein the pharmaceutical composition is co-administered to thepatient with a gastric acid-reducing agent. Embodiment MT4 is the methodaccording to Embodiment MT3, wherein the gastric acid-reducing agent isadministered to the patient shortly before the pharmaceuticalcomposition is administered. Embodiment MT5 is the method according toEmbodiment MT3, wherein the gastric acid-reducing agent is administeredto the patient concurrently with the administration of thepharmaceutical composition. Embodiment MT6 is the method according toEmbodiment MT3, wherein the gastric acid-reducing agent is administeredto the patient shortly after the pharmaceutical composition isadministered. Embodiment MT7 is the method according to any ofEmbodiments MT3 to MT6, wherein the gastric acid-reducing agent isselected from an H₂ antagonist, a proton pump inhibitor, and an antacid.

Embodiment MT8 is the method according to any of Embodiments MT3 to MT7,wherein a single administration to the patient of the pharmaceuticalcomposition concurrently with or shortly after a gastric-acid reducingagent results in an area-under-the-curve (AUC) of dasatinib that iswithin 50% of the AUC of dasatinib that results from administration ofthe pharmaceutical composition without concurrent administration of thegastric acid-reducing agent. Embodiment MT9 is the method according toany of Embodiments MT3 to MT7, wherein single administration to thepatient of the pharmaceutical composition concurrently with or shortlyafter a gastric-acid reducing agent results in a maximum plasmaconcentration (C_(max)) of dasatinib that is within 50% of the C_(max)of dasatinib that results from administration of the pharmaceuticalcomposition without concurrent administration of the gastricacid-reducing agent. Embodiment MT10 is the method according to any ofEmbodiments MT3 to MT7, wherein single administration to the patient ofthe pharmaceutical composition concurrently with or shortly after agastric-acid reducing agent results in an area-under-the-curve (AUC) ofdasatinib that is at least 100% greater than the AUC of dasatinib thatresults from administration of the standard commercial,immediate-release composition of dasatinib concurrently with thegastric-acid reducing agent, wherein the pharmaceutical compositioncontains the same dasatinib dosage as the standard commercial,immediate-release composition of dasatinib. Embodiment MT11 is themethod according to any of Embodiments MT3 to MT7, wherein singleadministration to the patient of the pharmaceutical compositionconcurrently with a gastric-acid reducing agent results in a maximumplasma concentration (C_(max)) of dasatinib that is at least 200%greater than the C_(max) of dasatinib that results from administrationof the standard commercial, immediate-release composition of dasatinibconcurrently with the gastric-acid reducing agent, wherein thepharmaceutical composition contains the same dasatinib dosage as thestandard commercial, immediate-release composition of dasatinib.

Embodiment MT12 is a method of treating a proliferative disorder in apatient in need thereof, the method comprising administering to thepatient a pharmaceutical composition according to any of Embodiments PC1to PC7, wherein the pharmaceutical composition is administered withoutregard to whether the patient has elevated gastric pH.

Embodiment MT13 is a method of treating a proliferative disorder in apatient in need thereof, the method comprising administering to thepatient a pharmaceutical composition according to any of Embodiments PC1to PC7; wherein the patient has elevated gastric pH.

Embodiment MT14 is a method of treating a proliferative disorder in apatient in need thereof, the method comprising: (a) identifying acondition by which the patient's gastric pH is chronically elevated; and(b) administering to the patient a therapeutically effective amount of apharmaceutical composition according to any of Embodiments PC1 to PC7;wherein the therapeutically effective amount comprises about 20 mg toabout 140 mg of dasatinib. Embodiment MT15 is the method according toEmbodiment MT14, wherein the condition by which the patient's gastric pHis elevated is achlorhydria or hypochlorhydria. Embodiment MT16 is themethod according to Embodiment MT14, wherein the condition by which thepatient's gastric pH is elevated is infection by Helicobacter pylori.

Embodiment MT17 is the method according to any of Embodiments MT13 toMT16, wherein single administration of the pharmaceutical compositionwhen the patient has elevated gastric pH results in anarea-under-the-curve (AUC) of dasatinib that is within 50% of the AUC ofdasatinib that results from administration of the pharmaceuticalcomposition when the patient does not have elevated gastric pH.Embodiment MT18 is the method according to any of Embodiments MT13 toMT16, wherein single administration of the pharmaceutical compositionwhen the patient has elevated gastric pH results in a maximum plasmaconcentration (C_(max)) of dasatinib that is within 50% of the C_(max)of dasatinib that results from administration of the pharmaceuticalcomposition when the patient does not have elevated gastric pH.Embodiment MT19 is the method according to any of Embodiments MT13 toMT16, wherein single administration of the pharmaceutical compositionwhen the patient has elevated gastric pH results in anarea-under-the-curve (AUC) of dasatinib that is at least 100% greaterthan the AUC of dasatinib that results from administration of thestandard commercial, immediate-release composition of dasatinib when thepatient has elevated gastric pH. Embodiment MT20 is the method accordingto any of Embodiments MT13 to MT16, wherein single administration of thepharmaceutical composition when the patient has elevated gastric pHresults in a maximum plasma concentration (C_(max)) of dasatinib that isat least 200% greater than the C_(max) of dasatinib that results fromadministration of the standard commercial, immediate-release compositionof dasatinib when the patient has elevated gastric pH.

Embodiment MT21 is the method according to any of Embodiments MT1 toMT20, wherein the proliferative disorder is cancer. Embodiment MT22 isthe method according to any of Embodiments MT1 to MT20, wherein theproliferative disorder is Philadelphia chromosome-positive chronicmyeloid leukemia. Embodiment MT23 is the method according to any ofEmbodiments MT1 to MT20, wherein the proliferative disorder isPhiladelphia chromosome-positive acute lymphoblastic leukemia.

Embodiment MS1 is a method of delivering a therapeutically relevantexposure of dasatinib to a subject without regard to whether the subjectis administered a gastric acid-reducing agent, the method comprisingadministering to the subject a pharmaceutical composition according toany of Embodiments PC1 to PC7.

Embodiment MS2 is a method of delivering a therapeutically relevantexposure of dasatinib to a subject, the method comprising administeringto the subject a pharmaceutical composition according to any ofEmbodiments PC1 to PC7, wherein the pharmaceutical composition isco-administered to the subject with the gastric acid-reducing agent.Embodiment MS3 is the method according to Embodiment MS2, wherein thegastric acid-reducing agent is administered to the subject shortlybefore the pharmaceutical composition is administered. Embodiment MS4 isthe method according to Embodiment MS2, wherein the gastricacid-reducing agent is administered to the subject concurrently with theadministration of the pharmaceutical composition. Embodiment MS5 is themethod according to Embodiment MS2, wherein the gastric acid-reducingagent is administered to the subject shortly after the pharmaceuticalcomposition is administered. Embodiment MS6 is the method according toany of Embodiments MS2 to MS5, wherein the gastric acid-reducing agentis selected from an H₂ antagonist, a proton pump inhibitor, and anantacid.

Embodiment MS7 is the method according to any of Embodiments MS2 to MS6,wherein a single administration to the subject of the pharmaceuticalcomposition concurrently with or shortly after a gastric-acid reducingagent results in an area-under-the-curve (AUC) of dasatinib that iswithin 50% of the AUC of dasatinib that results from administration ofthe pharmaceutical composition without concurrent administration of thegastric acid-reducing agent. Embodiment MS8 is the method according toany of Embodiments MS2 to MS6, wherein single administration to thesubject of the pharmaceutical composition concurrently with or shortlyafter a gastric-acid reducing agent results in a maximum plasmaconcentration (C_(max)) of dasatinib that is within 50% of the C_(max)of dasatinib that results from administration of the pharmaceuticalcomposition without concurrent administration of the gastricacid-reducing agent. Embodiment MS9 is the method according to any ofEmbodiments MS2 to MS6, wherein single administration to the subject ofthe pharmaceutical composition concurrently with or shortly after agastric-acid reducing agent results in an area-under-the-curve (AUC) ofdasatinib that is at least 100% greater than the AUC of dasatinib thatresults from administration of the standard commercial,immediate-release composition of dasatinib concurrently with thegastric-acid reducing agent, wherein the pharmaceutical compositioncontains the same dasatinib dosage as the standard commercial,immediate-release composition of dasatinib. Embodiment MS10 is themethod according to any of Embodiments MS2 to MS6, wherein singleadministration to the subject of the pharmaceutical compositionconcurrently with a gastric-acid reducing agent results in a maximumplasma concentration (C_(max)) of dasatinib that is at least 200%greater than the C_(max) of dasatinib that results from administrationof the standard commercial, immediate-release composition of dasatinibconcurrently with the gastric-acid reducing agent, wherein thepharmaceutical composition contains the same dasatinib dosage as thestandard commercial, immediate-release composition of dasatinib.

Embodiment MS11 is a method of delivering a therapeutically relevantexposure of dasatinib to a subject without regard to whether the subjecthas elevated gastric pH, the method comprising administering to thesubject a pharmaceutical composition according to any of Embodiments PC1to PC7.

Embodiment MS12 is a method of delivering a therapeutically relevantexposure of dasatinib to a subject who has elevated gastric pH, themethod comprising administering to the subject a pharmaceuticalcomposition according to any of Embodiments PC1 to PC7.

Embodiment MS13 is the method according to any of Embodiments MS11 toMS12, wherein single administration of the pharmaceutical compositionwhen the subject has elevated gastric pH results in anarea-under-the-curve (AUC) of dasatinib that is within 50% of the AUC ofdasatinib that results from administration of the pharmaceuticalcomposition when the subject does not have elevated gastric pH.Embodiment MS14 is the method according to any of Embodiments MT11 toMT12, wherein single administration of the pharmaceutical compositionwhen the subject has elevated gastric pH results in a maximum plasmaconcentration (C_(max)) of dasatinib that is within 50% of the C_(max)of dasatinib that results from administration of the pharmaceuticalcomposition when the subject does not have elevated gastric pH.Embodiment MS15 is the method according to any of Embodiments MT11 toMT12, wherein single administration of the pharmaceutical compositionwhen the subject has elevated gastric pH results in anarea-under-the-curve (AUC) of dasatinib that is at least 100% greaterthan the AUC of dasatinib that results from administration of thestandard commercial, immediate-release composition of dasatinib when thesubject has elevated gastric pH. Embodiment MS16 is the method accordingto any of Embodiments MT11 to MT12, wherein single administration of thepharmaceutical composition when the subject has elevated gastric pHresults in a maximum plasma concentration (C_(max)) of dasatinib that isat least 200% greater than the C_(max) of dasatinib that results fromadministration of the standard commercial, immediate-release compositionof dasatinib when the subject has elevated gastric pH.

Embodiment TR1 is a treatment regimen for treating a proliferativedisorder in a patient in need thereof, the regimen comprising: (a)administering to the patient a first dose, the first dose comprising astandard dosage of a proton pump inhibitor or H₂ antagonist; and (b)within 20 hours after the first dose, administering a second dose to thepatient, the second dose comprising a therapeutically effective amountof a pharmaceutical composition according to any of Embodiments PC1 toPC7, wherein the therapeutically effective amount comprises about 20 mgto about 140 mg dasatinib. Embodiment TR2 is the treatment regimenaccording to Embodiment TR1, wherein the second dose is administeredwithin 16 hours after the first dose. Embodiment TR3 is the treatmentregimen according to Embodiment TR1, wherein the second dose isadministered within 12 hours after the first dose. Embodiment TR4 is thetreatment regimen according to Embodiment TR1, wherein the second doseis administered within 8 hours after the first dose. Embodiment TR5 isthe treatment regimen according to Embodiment TR1, wherein the seconddose is administered within 6 hours after the first dose. Embodiment TR6is the treatment regimen according to Embodiment TR1, wherein the seconddose is administered within 4 hours after the first dose. Embodiment TR7is the treatment regimen according to Embodiment TR1, wherein the seconddose is administered within 2 hours after the first dose.

Embodiment TR8 is the treatment regimen according to any of EmbodimentsTR1 to TR7, wherein the first dose comprises a standard dosage of aproton pump inhibitor selected from rabeprazole, esomeprazole,lansoprazole, omeprazole, pantoprazole, dexlansoprazole, or acombination thereof. Embodiment TR9 is the treatment regimen accordingto any of Embodiments TR1 to TR7, wherein the first dose comprises astandard dosage of omeprazole. Embodiment TR10 is the treatment regimenaccording to any of Embodiments TR1 to TR7, wherein the first dosecomprises a standard dosage of an H₂ antagonist selected fromfamotidine, cimetidine, nizatidine, ranitidine, or a combinationthereof. Embodiment TR11 is the treatment regimen according to any ofEmbodiments TR1 to TR7, wherein the first dose comprises a standarddosage of famotidine.

Embodiment TR12 is a treatment regimen for treating a proliferativedisorder in a patient in need thereof, the regimen comprising: (a)administering to the patient a first dose, the first dose comprising astandard dosage of an antacid; and (b) within 2 hours before or 2 hoursafter the first dose, administering a second dose to the patient, thesecond dose comprising a pharmaceutical composition according to any ofEmbodiments PC1 to PC7; wherein the administration of the second doseprovides a therapeutically relevant exposure of dasatinib to thepatient.

Embodiment TR13 is the treatment regimen according to any of EmbodimentsTR1 to TR12, wherein the proliferative disorder is cancer. EmbodimentTR14 is the treatment regimen according to any of Embodiments TR1 toTR12, wherein the proliferative disorder is Philadelphiachromosome-positive chronic myeloid leukemia. Embodiment TR15 is thetreatment regimen according to any of Embodiments TR1 to TR12, whereinthe proliferative disorder is Philadelphia chromosome-positive acutelymphoblastic leukemia.

Embodiment KT1 is a kit for sale to a user, the kit comprising apharmaceutical composition according to any of Embodiments PC1 to PC7and a package insert, wherein the package insert informs the user thatthe pharmaceutical composition can be co-administered with a gastricacid-reducing agent.

Embodiment KT2 is a kit for sale to a user, the kit comprising apharmaceutical composition according to any of Embodiments PC1 to PC7and a package insert, wherein the package insert does not comprise awarning that the pharmaceutical composition should not beco-administered with H₂ antagonists or proton pump inhibitors.

Embodiment KT3 is a kit for sale to a user, the kit comprising apharmaceutical composition according to any of Embodiments PC1 to PC7and a package insert, wherein the package insert informs the user thatthe pharmaceutical composition can be suitably administered if the userhas chronically elevated gastric pH.

Embodiment KT4 is a kit for sale to a user, the kit comprising apharmaceutical composition according to any of Embodiments PC1 to PC7and a package insert, wherein package insert informs the user that thepharmaceutical composition can be suitably administered if the user hasbeen diagnosed with or is afflicted by achlorhydria or hypochlorhydria.

Embodiment KT5 is a kit for sale to a user, the kit comprising apharmaceutical composition according to any of Embodiments PC1 to PC7and a package insert, wherein the package insert informs the user thatthe pharmaceutical composition can be suitably administered if the userhas been diagnosed with or is afflicted by Helicobacter pyloriinfection.

EXAMPLES

Objects and advantages of this disclosure are further illustrated by thefollowing examples, but the particular materials and amounts thereofrecited in these examples, as well as other conditions and details,should not be construed to unduly limit this disclosure.

Example 1. Amorphicity and Stability of Dasatinib ASDs

A study was performed to investigate the impact of drug load on thechemical and physical stability of six different ASDs comprisingdasatinib and either EUDRAGIT L100-55 or EUDRAGIT E100 as the polymer.The drug:polymer ratio in the ASDs were 50:50, 60:40, or 70:30 (w/w).

To prepare the ASDs, appropriate quantities of dasatinib monohydrate andpolymer were dissolved in a 50:50 (v/v) solvent mixture of ethanol andmethanol to provide a liquid feedstock having a drug concentration of 4mg/mL. The ASDs were formed by electrospraying the liquid feedstockusing the Nanocopoeia spray machine ENS-P. The ENS-P machine utilizedsix nozzle slots, which were arranged in a circular array. Each nozzlehad twenty-four tips (D24). For each spray run, the spray processparameters, such as extractor voltage and flow rate, were adjusted toachieve an acceptable spray plume.

Each of the resulting ASDs was placed on stability under acceleratedconditions at 40° C./75% RH. The ASDs were assessed at t=0, 2 weeks, 1month, 2 months, and 3 months for appearance, amorphicity, loss ondrying, glass transition temperature, assay/impurities, and particlemorphology.

Appearance

Each ASD was assessed for physical appearance post-spray (t=0) and ateach time point on stability. All six ASDs were white to off-whitepowders at t=0 and showed no visible change on stability.

Amorphicity

Amorphicity (i.e., the lack of crystallinity) for the ASDs was assessedby XRD. Diffraction patterns were obtained using a Rigaku MiniFlex 600.The X-ray source was a long anode Cu Kα. Samples were prepared byplacing a small amount of ASD powder on a Rigaku zero-background sampleholder with a 0.1 mm indent. A glass slide was then used to firmly packthe powder and ensure the surface of the sample was level with the edgeof the sample holder.

Rigaku Data Analysis Software PDXL 2.4.2.0 was used to determine percentcrystallinity. Briefly, a linear background was obtained by connectingthe beginning and end of each diffractogram. Peaks were then fitted tosplit pseudo-Voigt shape by the Lorentzian function. Generally, narrowpeaks with full width at half maximum (FWHM) less than 1° were assignedas crystalline phase. Amorphous halos had FWHM greater than 1°,typically greater than 5°. The percent of crystallinity was calculatedas follows:% crystallinity=area of crystalline peaks/(area of crystallinepeaks+amorphous peaks)

The analysis found that all ASDs remained completely amorphous for threemonths at 40° C./75% RH, regardless of the drug load or the polymer.

Loss on Drying

Loss on drying (LOD) was assessed using thermogravimetric analysis(TGA), using a TA Instruments Model Q500. In general, about 5-10 mg ofASD material was loaded in a platinum sample pan.

Each of the ASDs was assessed for LOD post-spray (t=0) and at each timepoint on stability. Because TGA simply measures sample weight loss as afunction of temperature, the technique provides a measure of the totalresidual solvent present but is not capable of distinguishing betweenorganic solvents and water. LOD results for the six ASDs are listed inTable 4.

TABLE 4 LOD (TGA) data summary for the compositions of Example 1. LOD (%weight loss) Dasatinib: Dasatinib: EUDRAGIT EUDRAGIT Time L100-55 E100Point 50:50 60:40 70:30 50:50 60:40 70:30 0 5.4 5.7 5.5 2.2 2.7 3.1 2weeks 7.0 7.3 7.3 3.2 3.5 3.9 1 month 6.6 7.1 7.3 3.2 3.5 4.2 2 months6.0 6.1 6.1 2.6 2.5 3.1 3 months 5.5 5.7 5.9 2.0 2.3 2.3

As demonstrated in Table 4, the EUDRAGIT L100-55 ASDs had higher levelsof residual solvent and/or moisture compared to EUDRAGIT E100 ASDs forall drug:polymer ratios. Despite some variability in the data, all ASDsdemonstrated consistent loss on drying throughout the stability study.

Glass Transition Temperature

Glass transition temperature (T_(g)) of the ASDs was analyzed usingmodulated differential scanning calorimetry (mDSC), which was run on aTA Instruments Model Q200 equipped with a RCS90 refrigerated coolingsystem. In general, about 5-10 mg of ASD powder was loaded in a TAT_(zero) low-mass aluminum pan and sealed with a T_(zero) lid.Instrument details and measurement conditions are provided in Table 5.The results of the mDSC analysis are provided in Table 6.

TABLE 5 TA Q200 DSC instrument and measurement conditions. ParameterConditions DSC Mode Modulated Test MDSC heat only Method Modulate +0.447° C. every 60 sec, Temperature ramp 3.00° C./min from 0.00° C. to200.00° C. Data Sampling Interval 0.20 sec

TABLE 6 Glass transition temperature data for the ASDs of Example 1.T_(g) (° C.) Dasatinib: Time EUDRAGIT L100-55 Dasatinib: EUDRAGIT E100Point 50:50 60:40 70:30 50:50 60:40 70:30 0 148.3 148.3 142.5 67.0 78.25Not detected 2 weeks 147.2 147.5 144.2 61.5 Not detected Not detected 1month 148.8 147.7 143.3 Not Not detected Not detected detected 2months >140 147.1 143.6 Not Not detected Not detected detected 3 months146.6 146.3 143.1 64.6 Not detected Not detected

For all three EUDRAGIT L100-55 ASDs, there was essentially no change inT_(g) on stability. In the case of EUDRAGIT E100 ASDs, thermal eventsconsistent with a glass transition temperature were identified in only afew samples. Despite the lack of a measurable T_(g) for many of thesamples, the EUDRAGIT E100 ASDs remained amorphous and showed no signsof change based on visual appearance over the entire three months onstability.

Assay/Impurities

Assay/impurities of the ASDs were assessed using both an Agilent 1200HPLC and a Waters Alliance e2695 HPLC. The instrument and measurementconditions are specified in Table 7, while the gradient profile islisted in Table 8.

TABLE 7 HPLC instrument and measurement conditions used for theassay/impurity analysis of Example 1. Parameter Condition Mobile Phase A0.1% Formic acid in water Mobile Phase B 0.1% Formic acid inacetonitrile Flow 0.7 mL/min, gradient Injection Volume 10 μL ColumnTemperature 55° C. Wavelength 324 nm Run Time 40 min

TABLE 8 HPLC instrument gradient profile used for the assay/impurityanalysis of Example 1. Time (min) % Mobile Phase A % Mobile Phase B 1.0085.0 15.0 15.00 50.0 50.0 25.00 40.0 60.0 32.00 10.0 90.0 35.00 10.090.0 35.10 85.0 15.0 40.00 85.0 15.0

Assay values are listed in Table 9 and total impurities are listed inTable 10 for each ASD at t=0 and at the 3-month stability time point.

TABLE 9 Assay (HPLC) data summary for the compositions in Example 1.Assay (% Label Claim) Dasatinib: Dasatinib: Time EUDRAGIT L100-55EUDRAGIT E100 Point 50:50 60:40 70:30 50:50 60:40 70:30 0 102.5 96.3102.0 87.6 92.7 92.9 3 months 100.9 93.8 98.4 86.7 87.1 91.6

TABLE 10 Total impurities (HPLC) data summary for the compositions inExample 1. Total Impurities (%) Dasatinib: Dasatinib: Time EUDRAGITL100-55 EUDRAGIT E100 Point 50:50 60:40 70:30 50:50 60:40 70:30 0 0.3620.389 0.358 0.861 0.943 1.051 3 months 0.446 0.576 0.601 0.841 0.8100.769

Table 10 shows that the EUDRAGIT L100-55 ASDs had slightly lower totalimpurity levels than the EUDRAGIT E100 ASDs at the 3-month time point.Total impurities levels did increase slightly with increasing drug loadfor the EUDRAGIT L100-55 ASDs; however, the differences were small.Conversely, there was no apparent impact of drug load on totalimpurities for the EUDRAGIT E100 ASDs.

Particle Morphology

Particle morphology of each ASD was analyzed using scanning electronmicroscopy (SEM) at t=0 and at all stability time points using a JEOLJSM-6010Plus/LV. A small amount of each ENS powder was coated with athin layer of platinum using a JEOL Sputter Coater prior to analysis.

Based on SEM images, the EUDRAGIT L100-55 ASD particles ranged in sizefrom approximately 200 nm-2 μm while the EUDRAGIT E100 ASD particlesranged in size from 500 nm-4 μm.

All ASDs appeared to maintain their morphology after open dish exposurefor several months under accelerated conditions. There were not anyclear changes to the ASD particles and no signs of particle fusion wereevident, suggesting that the ASDs remained physically stable. This datawas in good agreement with the physical appearance and XRD assessments,which indicated neither observable change in the powders nor anyconversion from the amorphous to the crystalline state on stability.

In a separate experiment, an ASD was prepared comprising dasatinib andpolyvinylpyrrolidone (PVP K25) as the polymer, using a similar techniqueas above, at a 50:50 drug:polymer ratio. This ASD was maintained underharsh 50° C./80% RH (open dish) conditions. After 2 weeks, the ASDexhibited some crystalline character; after 4 weeks, a significantportion of the material had converted to crystalline.

Example 2. Long-Term Stability of Dasatinib ASDs Under AcceleratedConditions

A study was performed to assess long-term physical and chemicalstability of ASDs containing dasatinib and EUDRAGIT L100-55 as thestabilizing polymer in w/w ratio of 60:40 (drug:polymer). To prepare theASDs, suitable quantities of dasatinib (anhydrous) and polymer weredissolved in a 40:10:50 (v/v/v) solvent mixture ofmethanol:ethanol:ethyl acetate to prepare a liquid feedstock at a drugconcentration of 12.83 mg/mL, which was electrosprayed similar toExample 1.

The resulting ASDs were evaluated under storage conditions of 25° C./60%RH, 25° C./protected, 40° C./75% RH, and 40° C./protected, at timepoints of 1 month, 3 months, and 6 months. ASDs stored at 25° C./60% RHand 25° C./protected were additionally evaluated at 9 months and 12months.

Aliquots of approximately 300 mg of ASD powder were manually filled into7 mL vials for each time point and condition. Vials exposed to thehumidity conditions were loosely capped (open dish) and maintained in anupright position inside the chamber. Protected conditions were achievedby sealing closed vials in aluminum pouches, which were also maintainedin an upright position.

Amorphicity, glass transition temperature, water content, LOD, andassay/impurities were evaluated for each sample. Amorphicity and glasstransition temperature were assessed using the methodology described inExample 1.

Water content was determined using a coulometric Karl Fischer Titration.Approximately 40-50 mg of ASD powder was weighed into a glass Strombolisample vial and the vial was immediately sealed with a foil coated vialcover, and a rubber vial cap cover was placed on top of the sample vial.LOD was evaluated using the Computrac Max 4000, in which approximately0.5 g of material was spread evenly across the sample pan.Assay/impurities of the ASDs were assessed using the instrumentparameters, measurement conditions, and gradient profile specified inTable 11.

TABLE 11 HPLC instrument and measurement conditions. Parameter ConditionColumn Waters XBridge C18, 3.0 × 150 mm, 3.5 μm particle size Flow rate0.7 mL/min Mobile Phase A 20 mM Ammonium Bicarbonate pH 9.0 Mobile PhaseB 100% Acetonitrile (ACN) Impurities Program Time (min) % A % B  0.00 955  6.00 80 20 28.00 60 40 35.00 0 100 35.01 95 5 40.00 95 5 InjectionVolume 10.0 μL Column Temperature 45° C. Detector Wavelength 324 nm ScanRange 190-400 nm

The results of this study are presented in Tables 12-15. LOD, which wasonly measured at t=0, was determined to be 2.14%.

Under each of the storage conditions, the ASDs demonstrated chemical andphysical stability for the entire length of the study.

TABLE 12 Evaluation of Dasatinib:EUDRAGIT L100-55 (60:40) ASD under 25°C./60% RH storage conditions. Test Initial 1 Month 3 Month 6 MonthAppearance Off-white powder Off-white powder Off-white powder Off-whitepowder XRD Crystallinity Amorphous Amorphous Amorphous Amorphous T_(g)(° C.) 146.36 146.57 147.06 144.19 Water Content (%) 1.64 5.94 6.36 6.15Assay (%) 100.1 96.2 93.4 93.0 Total Impurities (%) 0.26 0.36 0.24 0.26

TABLE 13 Evaluation of Dasatinib:EUDRAGIT L100-55 (60:40) ASD under 25°C./protected storage conditions. Test Initial 1 Month 3 Month 6 MonthAppearance Off-white powder Off-white powder Off-white powder Off-whitepowder XRD Crystallinity Amorphous Amorphous Amorphous Amorphous T_(g)(° C.) 146.36 146.87 146.51 146.38 Water Content (%) 1.64 2.27 3.52 2.58Assay (%) 100.1 101.3 96.4 97.3 Total Impurities (%) 0.26 0.30 0.24 0.25

TABLE 14 Evaluation of Dasatinib:EUDRAGIT L100-55 (60:40) ASD under 40°C./75% RH storage conditions. Test Initial 1 Month 3 Month 6 MonthAppearance Off-white powder Off-white powder Off-white powder Off-whitepowder XRD Crystallinity Amorphous Amorphous Amorphous Amorphous T_(g)(° C.) 146.36 145.69 147.24 148.09 Water Content (%) 1.64 8.03 7.65 7.21Assay (%) 100.1 93.6 91.9 94.0 Total Impurities (%) 0.26 0.21 0.21 0.28

TABLE 15 Evaluation of Dasatinib:EUDRAGIT L100-55 (60:40) ASD under 40°C./protected storage conditions. Test Initial 1 Month 3 Month 6 MonthAppearance Off-white powder Off-white powder Off-white powder Off-whitepowder XRD Crystallinity Amorphous Amorphous Amorphous Amorphous T_(g)(° C.) 146.36 146.23 146.03 146.59 Water Content (%) 1.64 3.00 4.06 3.50Assay (%) 100.1 101.8 95.8 96.2 Total Impurities (%) 0.26 0.32 0.25 0.28

Example 3. In Vitro Dissolution of Dasatinib ASDs

A study was performed to investigate the in vitro dissolutionperformance of ASDs comprising dasatinib with EUDRAGIT L100-55 at aratio of 60:40 (w/w), and comprising dasatinib with EUDRAGIT E100 at aratio of 50:50 (w/w). SPRYCEL, the reference listed drug, was alsoincluded in the study as a benchmark, in the form of powder prepared bymanually crushing a suitable number of tablets.

To prepare the EUDRAGIT L100-55 ASD, a liquid feedstock was prepared bydissolving appropriate quantities of dasatinib (anhydrous) and polymerin a 65:20:15 (v/v/v) solvent mixture of methanol:ethanol:MEK to providea drug concentration of 15 mg/mL. To prepare the EUDRAGIT E100 ASD, aliquid feedstock was prepared by dissolving appropriate quantities ofdasatinib (anhydrous) and polymer in a 65:35 (v/v) solvent mixture ofmethanol:MEK to provide a drug concentration of 7.5 mg/mL. ASDs werethen formed by electrospraying the respective liquid feedstocks usingthe Nanocopoeia spray machine ENS-P. The ENS-P machine utilized sixnozzle slots, which were arranged in a circular array. Each nozzle hadtwenty-four tips (D24). For each spray run, the spray processparameters, such as extractor voltage and flow rate, were adjusted toachieve an acceptable spray plume.

For the in vitro study, a two-stage dissolution method was developed tomimic conditions in the stomach and upper intestine, and to mimic atransition between the two regions of the gastrointestinal tract. Thefirst-stage dissolution was conducted in Fasted State Simulated GastricFluid (FaSSGF) using three media that differed only in pH: Medium A (pH1.6), Medium B (pH 4.0), and Medium C (pH 6.0). Three Transition Media(D, E, and F) were developed to convert the three FaSSGF media to thesecond stage dissolution medium, Fasted State Simulated Intestinal Fluid(FaSSIF).

For the two-stage dissolution, a Vankel model VK7000 dissolution bathwas fitted with a USP Apparatus II system equipped with mini-vessels andmini-paddles. A Rainbow Dynamic Dissolution Monitor System (DelphianTechnology Inc., Woburn, Mass.) was used to monitor the solutionconcentration of dasatinib in situ. The Rainbow system contains aCathodeon Type J75 Deuterium (D2) lamp that transmits its signal viafurcation cable to supply the primary signals to six stainless steelprobes (20 mm path). A probe was positioned in each dissolution vessel.Samples were quantified against a 7-point standard curve that wasdeveloped for each ASD at each dissolution stage.

The compositions of the three FaSSGF Media (A, B, and C) used for thefirst-stage dissolution are listed in Table 16.

TABLE 16 Compositions of first-stage dissolution FaSSGF Media A, B, andC. Component FaSSGF A (pH 1.6) FaSSGF B (pH 4.0) FaSSGF C (pH 6.0)FaSSGF Instant Powder 60.0 mg 60.0 mg 60.0 mg NaCl 2.00 g 2.00 g 2.00 gHCl/NaOH Solution q.s. to pH 1.6 q.s. to pH 4.0 q.s. to pH 6.0 DeionizedH₂O q.s. to 1 L q.s. to 1 L q.s. to 1 L

For the dissolution procedure, 75 mL of one FaSSGF Medium (A, B, or C)was filled into a dissolution vessel, and then a sample (ASD or SPRYCELpowder) was accurately weighed to provide 42 mg dasatinib (sample weightvaried with sample composition drug load) for each vessel. Dasatinibconcentrations were measured at 10, 20, and 30 minutes afterintroduction of the sample to the vessel.

The compositions of the three Transition Media (D, E, and F) used toconvert the three FaSSGF media to the second stage dissolution medium(FaSSIF) are listed in Table 17.

TABLE 17 Composition of Transition Media D, E, and F. TransitionTransition Transition Component Medium D Medium E Medium F FaSSGF-V2Instant 6.98 g 6.98 g 6.98 g Powder NaCl 10.0 g 10.0 g 10.0 g MaleicAcid 8.88 g 8.88 g 8.88 g NaOH 9.45 g 5.77 g 5.80 g Deionized H₂O q.s.to 1 L q.s. to 1 L q.s. to 1 L

The second-stage dissolution medium, FaSSIF, was prepared by adding 25mL of the appropriate Transition Medium to 75 mL of the correspondingfirst-stage FaSSGF Medium, as summarized in Table 18. The resultingcomposition of FaSSIF was the same for all three combinations (A+D, B+E,and C+F) and the pH of the FaSSIF media in each case was 6.4.

TABLE 18 Composition of second-stage dissolution medium (FaSSIF).Component Quantity FaSSGF-V2 Instant Powder 174.5 mg FaSSGF InstantPowder 4.50 mg NaCl 400 mg Maleic Acid 222 mg NaOH 236.25 mg HCl/NaOHSolution q.s. pH 6.4 Deionized H₂O q.s. to 100 mL

For the second-stage dissolution procedure, 25 mL of the appropriateTransition Medium (D, E, or F) was added to the respective vessel 30minutes after the addition of the ASD sample. Dasatinib concentrationswere measured at 45, 60, and 90 minutes (elapsed time from introductionof the sample to the vessel). The data reported in the figures asdescribed below is expressed as a percentage of dasatinib measured insolution relative to the total dasatinib introduced into the vessel.

Transition of FaSSGF (pH 1.6) to FaSSIF (pH 6.4)

The dissolved drug-time profiles for dasatinib in FaSSGF (pH 1.6)transitioned to FaSSIF (pH 6.4) are presented in FIG. 1. Each of theASDs and SPRYCEL released nearly all of the dasatinib into solution inthe first 10 minutes and maintained relatively steady concentrationsuntil the transition to FaSSIF at t=30 min. For SPRYCEL, this result wasexpected based upon the known moderate solubility of dasatinib in acidicenvironments. That the ASDs also released nearly all of the dasatinib inthe first 10 minutes at pH 1.6 was unexpected, in light of the poorsolubility of EUDRAGIT L100-55 in acidic environments.

However, following the transition from FaSSGF to FaSSIF at t=30 min, theresult was different for SPRYCEL compared to the ASDs. In the case ofSPRYCEL, only approximately 10% of the dasatinib remained in solutionafter 90 minutes, presumably as a result of the known poor solubility ofdasatinib at neutral pH. In contrast, the ASDs were able to maintainmuch higher dasatinib concentrations in solution, ranging from 70%-80%for EUDRAGIT L100-55 ASD and 90%-100% for EUDRAGIT E100 ASD.

Transition of FaSSGF (pH 4.0) to FaSSIF (pH 6.4)

The dissolved drug-time profiles for dasatinib in FaSSGF (pH 4.0) toFaSSIF (pH 6.4) are presented in FIG. 2. Each of the ASDs and SPRYCELreleased dasatinib into solution to a much lower extent in FaSSGF withthe pH adjusted to 4.0 as compared to the same medium at pH 1.6 (FIG.1). SPRYCEL and EUDRAGIT L100-55 ASD achieved very similarconcentrations after 10 minutes (approximately 7%), which was maintaineduntil the transition to FaSSIF at t=30 min. The EUDRAGIT E100 ASDreleased dasatinib to a lesser extent and achieved a slightly lowerdasatinib concentration by 30 minutes (approximately 5%).

Upon addition of the transition media at t=30 min, the solutionconcentration of dasatinib quickly dropped for SPRYCEL, ultimatelyreducing to approximately 2% after 90 minutes. In contrast, the solutionconcentration of dasatinib increased for the ASDs following transitionto FaSSIF. Although the increases were modest, the ASDs were able tomaintain solution concentrations of 9%-10% after 90 minutes.

Transition of FaSSGF (pH 6.0) to FaSSIF (pH 6.4)

The dissolved drug-time profiles for dasatinib in FaSSGF (pH 6.0) toFaSSIF (pH 6.4) are presented in FIG. 3. Release of dasatinib intosolution in FaSSGF at pH 6.0 was even lower than that observed in the pH4.0 medium. As shown in FIG. 3, SPRYCEL released almost no dasatinibinto solution in either the first or second stage of dissolution. Thisresult was not unexpected based on the similar pH conditions for FaSSGFand FaSSIF in this experiment and the known low dasatinib solubility atnear-neutral pH conditions.

Each of the ASDs and SPRYCEL achieved concentrations of approximately3%-4% in neutral FaSSGF. However, significantly higher dasatinibsolution concentrations were achieved for the ASDs upon transition toFaSSIF when compared to SPRYCEL. The dasatinib solution concentrationslowly increased for the EUDRAGIT E100 ASD, ultimately achievingapproximately 7% after 90 minutes, while the EUDRAGIT L100-55 ASDachieved approximately 13% in solution after 90 minutes.

Taken together, these results demonstrate that, at low pH, each of theASDs and SPRYCEL were shown to have good dissolution in FaSSGF,achieving dasatinib concentration above 80%. However, following thetransition to FaSSIF, the two ASDs significantly outperformed SPRYCEL.At the intermediate and high pH FaSSGF conditions, each of the ASDs andSPRYCEL performed similarly initially; however, the ASDs outperformedSPRYCEL upon transition to the neutral pH FaSSIF.

Example 4. Canine In Vivo Studies

An in vivo study was performed on canine subjects to investigate theimpact of stomach pH on the pharmacokinetics observed uponadministration of dasatinib ASDs. The study included an ASDs comprisingdasatinib with EUDRAGIT L100-55 at a ratio of 60:40 (w/w), an ASDcomprising dasatinib with EUDRAGIT E100 at a ratio of 50:50 (w/w), andSPRYCEL (prepared as described below). ASDs were generated usingelectrospray techniques similar to prior Examples.

The pharmacokinetics of the three test compositions (two ASDs andSPRYCEL) was evaluated in male beagle dogs. The study incorporatedpentagastrin and famotidine pretreatments to adjust the stomach pH ofthe dogs prior to dosing. Based on published protocols, the pentagastrinpretreatment was expected to control the pH to a range between 1 and 2,while the famotidine pretreatment was expected to control the pH to arange between 6 and 8. Thus, in all, there were six legs to thestudy—each of the three compositions administered with each of the twopretreatments.

A summary of the study design is provided in Table 19. The studyemployed a crossover study design, with the same dogs receiving eachdose following a one-week washout period between each leg of the study.

Dogs were fasted for a minimum of twelve hours prior to doseadministration. Dogs were supplied with water ad libitum, and werehoused one per cage. Each study leg had five dogs. In study legs 1, 2,and 5, dogs were pretreated with famotidine (40 mg oral tablet)administered three hours prior to dosing of the test composition. Instudy legs, 3, 4, and 6 dogs were pretreated with pentagastrin (6 μg/kgdose, intramuscular injection) 30 minutes prior to dosing of the testcomposition. Each dog then received an appropriate oral dose of one ofthe test compositions at time zero. Following dosing, blood samples werecollected at 5, 15, 30, 45 minutes, 1, 2, 4, 6, 10, 16, 24, 36 hours.

TABLE 19 Study design for Example 4. Dose Blood Dose Concen- DosingSampling Study Pre- (mg/ tration Volume Time Leg Composition treatmentkg) (mg/mL) (mL/g) Points 1 SPRYCEL Famotidine 5 9.644 0.5 Pre-dose, 2Dasatinib: Famotidine  5 min, EUDRAGIT 15 min, L100-55 30 min, 60:40 ASD45 min, 3 SPRYCEL Pentagastrin  1 hour, 4 Dasatinib: Pentagastrin  2hours, EUDRAGIT  4 hours, L100-55  6 hours, 60:40 ASD 10 hours, 5Dasatinib: Famotidine 16 hours, EUDRAGIT 24 hours, E100 50:50 36 hoursASD 6 Dasatinib: Pentagastrin EUDRAGIT E100 50:50 ASD

Test compositions were orally dosed as suspensions comprising a bufferedaqueous vehicle. Vehicles used for each composition are provided inTable 20. For the SPRYCEL test composition, the SPRYCEL tablets werecrushed and mixed with the vehicle. All test composition suspensionswere prepared at a final dasatinib concentration of 9.64 mg/mL and wereprepared fresh on the day of dosing.

TABLE 20 Dosing vehicles for study legs 1-6 for Example 4. Study Pre-Leg Composition treatment Vehicle 1 SPRYCEL Famotidine 0.5%methylcellulose in (crushed) 1 mM phosphate buffer 2 ASD Famotidine 0.5%methylcellulose in (EUDRAGIT L100-55) 0.5 mM citric acid buffer 3SPRYCEL Pentagastrin 0.5% methylcellulose in (crushed) 1 mM phosphatebuffer 4 ASD Pentagastrin 0.5% methylcellulose in (EUDRAGIT L100-55) 0.5mM citric acid buffer 5 ASD Famotidine 0.5% methylcellulose in (EUDRAGITE100) 1 mM phosphate buffer 6 ASD Pentagastrin 0.5% methylcellulose in(EUDRAGIT E100) 1 mM phosphate bufferPharmacokinetics

Pharmacokinetic parameters were calculated from the time course of theplasma concentrations. The maximum plasma concentration (C_(max)) andthe time to reach maximum plasma drug concentration (T_(max)) after oraldosing were determined from the data. Any samples for which the plasmaconcentration was below the limit of quantitation (0.5 ng/mL) weretreated as zero for pharmacokinetic data analysis.

The original study protocol called for approximately 1 mL of gastricfluid to be aspirated for pH measurement. However, following leg 1, itwas apparent that there was very little fluid in the stomach of the dogsand that the procedure was traumatic to the animals. For this reason, itwas decided that gastric fluid samples would not be acquired for studylegs 2 through 6.

Calculated pharmacokinetic parameters are given in Tables 21 through 26.The tables below include the following abbreviations and notations:

C_(max): maximum plasma concentration;

t_(max): time of maximum plasma concentration;

t_(1/2): half-life;

MRT_(last): mean residence time, calculated to the last observable timepoint;

AUC_(last): area under the curve, calculated to the last observable timepoint;

AUC_(0-inf): area under the curve, extrapolated to infinity;

ND: not determined.

TABLE 21 Individual and average pharmacokinetic parameters for Leg 1 ofExample 4. Famotidine Pretreatment-SPRYCEL Dog Dog Dog Dog DogParameters 1 2 3 4 5 Mean SD Animal 10.3 11.5  13.4  14.0 11.5 12.1 1.5  Weight (kg) Volume 5.2  5.8   6.7  7.0 5.8 6.1  0.7  Dose (mL)C_(max) 1.92  1.84  2.20 3.95 5.94 3.17  1.77 (ng/mL) t_(max) (hr) 1.016   10   2.0 24 11  9.7  t_(1/2) (hr) 5.86 ND^(b) ND^(b) 12.4 ND^(b)9.16 ND MRT_(last) 7.47 12.6   8.53 6.30 21.3 11.2  6.08 (hr) AUC_(last)19.1 27.9  25.3  27.3 98.9 39.7 33.3  (hr · ng/ mL) AUC_(0-inf) 23.4ND^(b) ND^(b) ND^(c) ND^(b) ND ND (hr · ng/ mL) Dose-normalizedvalues^(a) AUC_(last) 3.82  5.58  5.06 5.46 19.8 7.94  6.66 (hr · kg ·ng/ mL/mg) AUC_(0-inf) 4.67 ND^(b) ND^(b) ND^(c) ND^(b) ND ND (hr · kg ·ng/ mL/mg) ^(a)Dose-normalized by dividing the parameter by the nominaldose in mg/kg; ^(b)not determined because the terminal elimination phasewas not observed; ^(c)not determined because the AUC_(0-inf) was agreater than 25% extrapolation above the AUC_(last).

TABLE 22 Individual and average pharmacokinetic parameters for Leg 2 ofExample 4. Famotidine Pretreatment-ASD (EUDRAGIT L100-55) Parameters Dog1 Dog 2 Dog 3 Dog 4 Dog 5 Mean SD Animal Weight 9.6 10.7 12.6 13.3 10.611.4 1.5 (kg) Volume Dose (mL) 4.8 5.4 6.3 6.7 5.3 5.7 0.8 C_(max)(ng/mL) 31.8 69.4 107 722 765 339 370 t_(max) (hr) 4.0 4.0 0.75 0.250.25 1.9 2.0 t_(1/2) (hr) 3.32 3.91 3.02 4.39 4.06 3.74 0.559 MRT_(last)(hr) 5.79 7.22 5.53 5.94 5.62 6.02 0.688 AUC_(last) 229 602 648 1411 941766 441 (hr · ng/mL) AUC_(0-inf) 232 615 653 1417 944 772 441 (hr ·ng/mL) Dose-normalized values^(a) AUC_(last) 45.8 120 130 282 188 15388.1 (hr · kg · ng/mL/mg) AUC_(0-inf) 46.3 123 131 283 189 154 88.1 (hr· kg · ng/mL/mg) ^(a)Dose-normalized by dividing the parameter by thenominal dose in mg/kg.

TABLE 23 Individual and average pharmacokinetic parameters for Leg 3 ofExample 4. Pentagastrin Pretreatment-SPRYCEL Parameters Dog 1 Dog 2 Dog3 Dog 4 Dog 5 Mean SD Animal Weight 10.0 10.7 13.2 13.1 10.6 11.5 1.5(kg) Volume Dose (mL) 5.0 5.4 6.6 6.6 5.3 5.8 0.8 C_(max) (ng/mL) 63.2208 55.8 166 66.4 112 70.3 t_(max) (hr) 4.0 0.25 2.0 0.50 0.083 1.4 1.7t_(1/2) (hr) 3.10 5.29 2.97 3.02 5.14 3.91 1.20 MRT_(last) (hr) 5.613.67 6.42 4.96 6.41 5.42 1.15 AUC_(last) 390 452 344 550 442 436 77.0(hr · ng/mL) AUC_(0-inf) 406 490 347 553 459 451 78.8 (hr · ng/mL)Dose-normalized values^(a) AUC_(last) 78.0 90.4 68.8 110 88.4 87.1 15.4(hr · kg · ng/mL/mg) AUC_(0-inf) 81.3 98.0 69.3 111 91.7 90.2 15.8 (hr ·kg · ng/mL/mg) ^(a)Dose-normalized by dividing the parameter by thenominal dose in mg/kg.

TABLE 24 Individual and average pharmacokinetic parameters for Leg 4 ofExample 4. Pentagastrin Pretreatment-ASD (EUDRAGIT L100-55) ParametersDog 1 Dog 2 Dog 3 Dog 4 Dog 5 Mean SD Animal Weight 10.2 10.9 13.0 13.110.5 11.5 1.4 (kg) Volume 5.1 5.5 6.5 6.6 5.3 5.8 0.7 Dose (mL) C_(max)(ng/mL) 88.8 72.5 11.5 101 144 83.6 48.2 t_(max) (hr) 4.0 2.0 2.0 2.00.25 2.1 1.3 t_(1/2) (hr) 3.62 4.49 3.33 2.93 4.07 3.69 0.614 MRT_(last)(hr) 6.95 7.07 4.95 5.32 3.96 5.65 1.34 AUC_(last) 620 678 81.8 662 236456 277 (hr · ng/mL) AUC_(0-inf) 630 699 84.8 665 248 465 280 (hr ·ng/mL) Dose-normalized values^(a) AUC_(last) 124 136 16.4 132 47.3 91.155.4 (hr · kg · ng/mL/mg) AUC_(0-inf) 126 140 17.0 133 49.7 93.1 56.0(hr · kg · ng/mL/mg) ^(a)Dose-normalized by dividing the parameter bythe nominal dose in mg/kg.

TABLE 25 Individual and average pharmacokinetic parameters for Leg 5 ofExample 4. Famotidine Pretreatment-ASD (EUDRAGIT E100) Parameters Dog 1Dog 2 Dog 3 Dog 4 Dog 5 Mean SD Animal Weight 10.2 10.6 12.9 13.0 10.511.4 1.4 (kg) Volume Dose (mL) 5.1 5.3 6.5 6.5 5.3 5.7 0.7 C_(max)(ng/mL) 153 178 71.1 305 19.5 145 110 t_(max) (hr) 0.5 0.25 2.0 0.5 1.00.9 0.7 t_(1/2) (hr) 4.58 3.97 3.48 5.30 2.19 3.90 1.18 MRT_(last) (hr)5.97 5.81 6.49 7.18 2.92 5.67 1.63 AUC_(last) (hr · ng/mL) 734 601 6031180 77.2 639 394 AUC_(0-inf) 752 607 611 1187 81.0 648 395 (hr · ng/mL)Dose-normalized values^(a) AUC_(last) 147 120 121 236 15.4 128 78.8 (hr· kg · ng/mL/mg) AUC_(0-inf) 150 121 122 237 16.2 130 79.1 (hr · kg ·ng/mL/mg) ^(a)Dose-normalized by dividing the parameter by the nominaldose in mg/kg.

TABLE 26 Individual and average pharmacokinetic parameters for Leg 6 ofExample 4. Pentagastrin Pretreatment-ASD (EUDRAGIT E100) Parameters Dog1 Dog 2 Dog 3 Dog 4 Dog 5 Mean SD Animal Weight 10.1 10.6 13.0 13.6 10.711.6 1.58 (kg) Volume Dose (mL) 5.1 5.3 6.5 6.8 5.4 5.82 0.773 C_(max)(ng/mL) 29.4 120 23.9 165 80.1 83.7 60.1 t_(max) (hr) 0.25 6.0 2.0 1.00.25 1.9 2.4 t_(1/2) (hr) 2.24 6.37 3.25 3.99 3.55 3.88 1.53 MRT_(last)(hr) 2.80 9.29 5.43 5.31 3.70 5.30 2.49 AUC_(last) 77.2 1262 146 680 193472 502 (hr · ng/mL) AUC_(0-inf) 80.8 1288 152 691 200 482 510 (hr ·ng/mL) Dose-normalized values^(a) AUC_(last) 15.4 252 29.2 136 38.7 94.3100 (hr · kg · ng/mL/mg) AUC_(0-inf) 16.2 258 30.4 138 40.1 96.5 102 (hr· kg · ng/mL/mg) ^(a)Dose-normalized by dividing the parameter by thenominal dose in mg/kg.

The pharmacokinetic profiles obtained from administration of the testcompositions and SPRYCEL are shown following pentagastrin pretreatmentin FIG. 4 and famotidine pretreatment in FIG. 5.

As shown in FIG. 4, all three compositions performed essentially thesame following pentagastrin pretreatment (i.e., at acidic pH). AverageC_(max) values were nearly identical for the two ASD compositions (83.6and 83.7 ng/mL) and just slightly lower than SPRYCEL (112 ng/mL).Similarly, dose normalized AUC_(last) values were in good agreementacross all three test compositions (observed range of 87.1 to 94.3hr·kg·ng/mL/mg), despite significant variability in the dog data. Thedata demonstrate that the absorption of dasatinib at conditions of lowpH was consistent for the three test compositions.

Surprisingly, the two ASD compositions performed similarly despiteEUDRAGIT L100-55 and EUDRAGIT E100 have very different polymerchemistry. EUDRAGIT E100 is known to be soluble in gastric fluid up topH 5.0, while EUDRAGIT L100-55 is known to be insoluble in gastric fluidup to pH 5.5. Based on this information, it was unexpected that theEUDRAGIT L100-55 ASD composition would release drug at the same rate orto the same extent as the EUDRAGIT E100 ASD composition under low pHconditions.

Pretreatment with famotidine led to much different results, as shown inFIG. 5. The performance of SPRYCEL was markedly different at neutral pHthan acidic pH. The C_(max) for SPRYCEL at neutral pH followingfamotidine pretreatment (3.2 ng/mL) was nearly two orders-of-magnitudelower than what was observed at acidic pH (112 ng/mL). Similarly, thedose normalized AUC_(last) for SPRYCEL was also dramatically lowerfollowing famotidine (7.94 hr·kg·ng/mL/mg) compared to pentagastrin(87.1 hr·kg·ng/mL/mg). These results were somewhat expected based uponpublished literature and the known poor solubility of dasatinib atelevated pH values.

In contrast, the two ASD compositions demonstrated significantly higherC_(max) and AUC values compared to SPRYCEL following famotidinepretreatment. C_(max) values for the two ASDs were highly variable butdramatically higher than SPRYCEL. Surprisingly, these peakconcentrations were also higher than what was observed followingpentagastrin pretreatment, despite the higher solubility of dasatinib atlow pH. Both ASD compositions achieved similar dose normalizedAUC_(last) values (153 ng/mL for EUDRAGIT L100-55 ASD and 128 ng/mL forEUDRAGIT E100 ASD) under neutral pH conditions, which were againdramatically higher than what was observed for SPRYCEL (7.94hr·kg·ng/mL/mg). The AUC values for the ASD compositions followingfamotidine pretreatment were also relatively consistent with the valuesobtained following pentagastrin pretreatment, which indicated that thepreparation of dasatinib in an ASD was capable of significantlydiminishing the effect of pH on dasatinib absorption kinetics.

Example 5. Human In Vivo Studies

A study was performed on human subjects to investigate the impact ofelevated gastric pH on the pharmacokinetics observed upon administrationof an ASD comprising dasatinib with EUDRAGIT L100-55 at a ratio of 60:40(w/w) as compared to SPRYCEL (100 mg tablet) in the fasted state.

The ASD was dosed by way of an immediate-release tablet comprising theASD. To prepare the ASD, appropriate quantities of dasatinib (anhydrous)and polymer were dissolved in a 1:1:1 (v/v/v) solvent mixture ofmethanol:ethanol:isopropyl acetate to provide a drug concentration of 1wt.-%. The ASD was prepared by an electrospray technique similar to thatused in prior Examples.

The resulting ASD was formulated into tablets containing 100 mgdasatinib. Granules were first formed by dry granulation of the ASD (50%w/w) with FUJICALIN, AVICEL PH-105, VIVASOL, AEROSIL R972, and magnesiumstearate. Suitable quantities of the dry components were bag-blended andthen roller-compacted to provide ribbons. Ribbons were processed throughan oscillating granulator and sieved to provide suitably sized granules(20-24 mesh). Then, a tableting formulation was prepared usingapproximately 80% (w/w) granules along with additional quantities ofAVICEL PH-105, VIVASOL, AEROSIL R972, and magnesium stearate. Theformulation components were thoroughly v-blended, and then tabletedusing a tablet press to provide tablets containing 100 mg dasatinib(“Dasatinib ASD Tablet”).

The human study employed a balanced, two-treatment, two period, twosequence, single dose, crossover design. Subjects were randomly dividedas to whether they would receive the Dasatinib ASD Tablet in the firststudy period and the SPRYCEL tablet in the second study period, or viceversa. In each study period, subjects under fasting conditions receiveda single oral 20-mg dose of famotidine approximately three hours priorto dosing with either Dasatinib ASD Tablet (100 mg) or with SPRYCEL (100mg) tablet. There was a washout period of 12 days between the twoperiods.

Plasma samples were taken within one hour prior to dosing with eitherthe Dasatinib ASD Tablet or SPRYCEL tablet. Post-dose plasma sampleswere taken at suitable timepoints for evaluating the pharmacokineticprofile, up to 24 hours. In all, 24 subjects participated in the study.

Plasma samples were analyzed for dasatinib content. Pharmacokineticparameters were calculated from the data. FIG. 6, which presents thepharmacokinetic profiles based on untransformed data, shows that therewas a substantial difference in the plasma concentrations of dasatinibafter administration of the Dasatinib ASD Tablet as compared to afteradministration of the SPRYCEL tablet. Calculated pharmacokineticparameters are presented in Table 27. These results show that subjectswho were pretreated with famotidine and therefore had elevated gastricpH experienced substantially greater AUC and C_(max) afteradministration of the Dasatinib ASD Tablet as compared to afteradministration of the SPRYCEL tablet, which resulted in very littledasatinib absorption.

TABLE 27 Calculated pharmacokinetic parameters at elevated gastric pHfor Example 5. % Ratio Mean (untransformed) ± SD (CV %) Dasatinib ASDDasatinib SPRYCEL Tablet/ Parameters ASD Tablet tablet SPRYCEL tabletAUC_(0-inf) 920.7 ± 220.3 (23.9) 157.6 ± 81.3 (51.7) 584 (ng × hr/mL)AUC_(last) 889.1 ± 215.4 (24.2)  80.8 ± 32.9 (40.7) 1100 (ng × hr/mL)C_(max) (ng/mL) 227.9 ± 69.6 (30.5)   7.97 ± 4.11 (51.6) 2860 t_(max)(hr) 2.9 ± 0.9    5.6 ± 7.2   n/a K_(el) (1/h) 0.153 ± 0.037    0.088 ±0.123   n/a t_(1/2) (hr) 4.9 ± 1.5    18.9 ± 15.0   n/a K_(el) =elimination rate constant n/a = not applicable

A separate study was performed similarly, except that subjects were notprovided a famotidine pretreatment, and accordingly did not haveartificially modified gastric pH. (It should be noted that the twostudies were done using different sets of subjects. Absorption ofdasatinib is observed to have a high degree of inter-subjectvariability.) Calculated pharmacokinetic parameters for this study arepresented in Table 28. Administration of Dasatinib ASD Tablet performedsimilarly to SPRYCEL tablet under these study conditions.

TABLE 28 Calculated pharmacokinetic parameters at unmodified gastric pHfor Example 5. % Ratio Mean (untransformed) ± SD (CV %) Dasatinib ASDDasatinib SPRYCEL Tablet/ Parameters ASD Tablet tablet SPRYCEL tabletAUC_(0-inf) 718.8 ± 152.0 (21.1) 657.9 ± 222.1 (33.8) 109 (ng × hr/mL)AUC_(last) 697.9 ± 149.9 (21.4) 602.4 ± 252.3 (41.8) 116 (ng × hr/mL)C_(max) (ng/mL) 168.6 ± 50.4 (29.9)  154.8 ± 66.2  (42.8) 109 t_(max)(hr) 2.2 ± 1.1     1.7 ± 1.1     n/a K_(el) (1/h) 0.155 ± 0.030    0.150 ± 0.041     n/a t_(1/2) (hr) 4.6 ± 0.9     5.0 ± 1.5     n/aK_(el) = elimination rate constant n/a = not applicable

FIG. 7 shows pharmacokinetic profiles for this study, as well as for theelevated-pH study, and demonstrates that the pharmacokinetic profileresulting from administration of the Dasatinib ASD Tablet is similarregardless of whether the subject had artificially elevated gastric pHor not. In other words, elevated gastric pH had little effect on theabsorption of dasatinib delivered via the Dasatinib ASD Tablet. Thiscontrasts with SPRYCEL tablet, for which a dramatic decrease in exposurewas observed after pretreatment with famotidine.

Notably, the pharmacokinetic profile and plasma concentration levelsresulting from administration of the Dasatinib ASD Tablet withfamotidine pretreatment resembled those resulting from administration ofSPRYCEL tablet without famotidine pretreatment.

FIGS. 8 and 9 are box plots graphically representing the respective AUC(FIG. 8) and C_(max) (FIG. 9) data and calculated statistical parametersfrom the two studies. These plots visually demonstrate that (i)Dasatinib ASD Tablet performed similarly regardless of whether thesubject had artificially elevated gastric pH or not; (ii) the DasatinibASD Tablet performed similarly to SPRYCEL tablet when gastric pH wasunmodified; and (iii) Dasatinib ASD Tablet outperformed SPRYCEL tabletwhen gastric pH was artificially elevated.

As can also be seen from FIGS. 8 and 9, at least one subject receivedalmost no exposure to SPRYCEL, even without famotidine pretreatment.(This data point is graphically represented by the black dot near thebottom of the scale for both AUC in FIG. 8 and C_(max) in FIG. 9.)Although not wishing to be bound, it is thought that this subjectsuffered from a condition that caused elevated gastric pH (such ashypochlorhydria or infection by H. pylori). If such a person wereprescribed dasatinib therapy using SPRYCEL, the person would not beexperiencing a therapeutic exposure of dasatinib. However, the samesubject did experience a significant exposure of dasatinib whenadministered the Dasatinib ASD Tablet, as that subject's exposure isincluded in the graphical representation to the far left of the boxplot.

Therefore, as a surprising and unexpected benefit, embodiments of thepresent disclosure can provide therapy to certain patients who mightotherwise not be receiving the benefit of dasatinib therapy if using theconventional commercially available immediate release formulation ofdasatinib.

Comparative Example

As a control, a spray-dried material of 100% dasatinib (i.e., nopolymer) was prepared. A feedstock comprising 8 mg/mL of anhydrousdasatinib dissolved in a 60:40 (v/v) solvent mixture of methanol:MEK wasprepared and spray-dried as with the amorphous solid dispersions inExample 6, below. After spray drying, the collected material was driedat 60° C. under vacuum for about 18 hours to remove residual solvents.

This spray-dried material was then promptly assessed by XRD, andexhibited crystalline character. The glass transition temperature(T_(g)) of the material was assessed, and a transition event wasdetected at 125.61° C. Water content was measured as 0.81% and themeasured assay value was 97.4%.

Because this material reverted to crystalline character essentiallyimmediately, it was not subjected to stability testing or furthercharacterization.

Example 6. Preparation and Stability of High Drug Load Dasatinib ASDs

A study was performed to investigate the impact of drug load on thechemical and physical stability of several different ASDs comprisingdasatinib and either EUDRAGIT L100-55 or METHOCEL E5 as the polymer. Forthis study, the drug:polymer ratio (w/w) in the ASDs were 70:30, 75:25,80:20, 85:15, 90:10.

To prepare the ASDs, appropriate quantities of anhydrous dasatinib andpolymer were dissolved in a 60:40 (v/v) solvent mixture of methanol:MEKto provide a liquid feedstock having a drug concentration of about 6 toabout 10 mg/mL and a total solids concentration of about 8 to about 15mg/mL. The ASDs were formed by spray drying the liquid feedstock using aBuchi B-290 spray dryer equipped with a two-fluid nozzle and a BuchiB-295 inert loop. For each spray run, the spray process parameters, suchas inlet temperature, pump rate, outlet temperature, etc. were adjustedto achieve an acceptable outcome. Inlet temperature was set at 115-125°C., pump rate was set at 20%, and outlet temperature was 70-85° C. Theresulting ASD was collected using a cyclone separator. After spraydrying, each ASD was dried at 60° C. under vacuum for about 18 hours toremove residual solvents.

Each of the resulting ASDs was placed on stability under acceleratedconditions at 40° C./75% RH. The ASDs were assessed at t=0 (i.e., afterthe secondary drying step), 2 weeks, 1 month, 2 months, 3 months, and 6months for appearance, amorphicity, glass transition temperature, watercontent, and assay/total impurities.

Appearance

Each ASD was assessed for physical appearance at the initiation of thestability study (t=0) and at each time point on stability. All ASDs werewhite to off-white powders at t=0 and showed no visible change afterstorage under accelerated conditions for 6 months.

Amorphicity

Amorphicity (i.e., the lack of crystallinity) for the ASDs was assessedby XRD. Diffraction patterns were obtained using a Rigaku MiniFlex 600.The X-ray source was a long anode Cu Kα. Samples were prepared byplacing a small amount of ASD powder on a Rigaku zero-background sampleholder with a 0.1 mm indent. A glass slide was then used to firmly packthe powder and ensure the surface of the sample was level with the edgeof the sample holder.

Rigaku Data Analysis Software PDXL 2.4.2.0 was used to determinecrystallinity. Briefly, a linear background was obtained by connectingthe beginning and end of each diffractogram. Peaks were then fitted tosplit pseudo-Voigt shape by the Lorentzian function. Generally, narrowpeaks with full width at half maximum (FWHM) less than 1° were assignedas crystalline phase. If no crystalline phase was detected, the samplewas deemed to be amorphous.

All Dasatinib:EUDRAGIT L100-55 ASDs remained completely amorphous afterstorage for six months at 40° C./75% RH, regardless of the drug load.

For Dasatinib:METHOCEL E5 ASDs, the 70:30 ASD showed some crystallinecharacter after storage for two months at 40° C./75% RH, and the 75:25and 80:20 ASDs showed some crystalline character after storage for sixmonths at 40° C./75% RH. However, the 85:15 and 90:10 ASDs remainedcompletely amorphous after storage for six months at 40° C./75% RH.

These results demonstrate that the higher drug load was beneficial forproviding physical stability under accelerated conditions for thesedasatinib ASDs, and indicate a promising approach for stability underreal-world storage conditions.

Glass Transition Temperature

Glass transition temperature (T_(g)) of the ASDs was analyzed usingmodulated differential scanning calorimetry (mDSC), which was run on aTA Instruments Model Q200 equipped with a RCS90 refrigerated coolingsystem. In general, about 5-10 mg of ASD powder was loaded in a TAT_(zero) low-mass aluminum pan and sealed with a T_(zero) lid.Instrument details and measurement conditions are provided in Table 29.The results of the mDSC analysis are provided in Tables 30 and 31.

TABLE 29 TA Q200 DSC instrument and measurement conditions. ParameterConditions DSC Mode Modulated Test MDSC heat only Method Modulate +0.48° C. every 60 sec, Temperature ramp 3.00° C./ min from 0.00° C. to200.00° C. Data Sampling Interval 0.20 sec

TABLE 30 Glass transition temperature data for the Dasatinib:EUDRAGITL100-55 ASDs of Example 6, stored at 40° C./75% RH through 6 months.T_(g) (° C.) Dasatinib:EUDRAGIT L100-55 Time Point 70:30 75:25 80:2085:15 90:10 0 136.55 132.83 128.93 134.14 133.03 2 weeks 138.61 137.73132.82 135.38 133.85 1 month 137.49 135.33 133.19 135.49 133.18 2 months138.74 134.33 134.01 134.96 132.63 3 months 140.38 137.87 134.33 135.76134.47 6 months 139.59 138.01 135.04 137.13 134.35

TABLE 31 Glass transition temperature data for the Dasatinib:METHOCEL E5ASDs of Example 6, stored at 40° C./75% RH through 6 months. T_(g) (°C.) Dasatinib:METHOCEL E5 Time Point 70:30 75:25 80:20 85:15 90:10 0119.62 119.61 119.77 127.58 128.42 2 weeks 124.39 123.79 123.58 127.92128.24 1 month 125.19 125.44 124.37 128.39 129.13 2 months 125.81 126.05125.91 128.86 129.51 3 months 126.91 125.62 125.88 129.46 129.63 6months 127.72 128.10 127.01 129.94 130.47

For all the ASDs, there was a slight change in T_(g) on stability, buteach sample did demonstrate a thermal event consistent with a glasstransition temperature.

Water Content

Water content was determined using a coulometric Karl Fischer Titration.Approximately 40-50 mg of ASD powder was weighed into a glass Strombolisample vial and the vial was immediately sealed with a foil coated vialcover, and a rubber vial cap cover was placed on top of the sample vial.

The results, presented in Tables 32 and 33, show that the water contentrose between t=0 and 2 weeks due to moisture absorption from thecontrolled environment. The water content then generally remained steadyfrom 2 weeks through 6 months, which indicates that the moisture in theamorphous solid dispersions had reached equilibrium with theenvironment.

TABLE 32 Water content data for the Dasatinib:EUDRAGIT L100-55 ASDs ofExample 6, stored at 40° C./75% RH through 6 months. Water Content (% byweight) Dasatinib:EUDRAGIT L100-55 Time Point 70:30 75:25 80:20 85:1590:10 0 0.47 0.44 0.39 1.08 1.26 2 weeks 7.16 7.18 6.94 7.11 6.72 1month 7.48 7.28 7.04 6.40 7.12 2 months 7.17 6.62 6.91 7.12 6.74 3months 7.29 7.26 7.03 7.06 6.71 6 months 7.65 7.69 7.43 5.27 5.33

TABLE 33 Water content data for the Dasatinib:METHOCEL E5 ASDs ofExample 6, stored at 40° C./75% RH through 6 months. Water Content (% byweight) Dasatinib:METHOCEL E5 Time Point 70:30 75:25 80:20 85:15 90:10 00.42 0.42 0.43 1.10 1.18 2 weeks 6.94 6.67 6.44 6.77 6.33 1 month 6.986.88 6.56 6.69 6.00 2 months 6.64 6.59 6.39 6.45 6.10 3 months 6.66 6.586.28 6.41 6.18 6 months 6.41 6.64 6.52 3.17 2.77Assay and Total Impurities

Assay and total impurities of the ASDs were assessed using either anAgilent 1200 HPLC or a Waters Alliance e2695 HPLC. The instrument andmeasurement conditions are specified in Table 34 and the gradientprofile in Table 35.

TABLE 34 HPLC instrument and measurement conditions used for theassay/impurity analysis of Example 6. Parameter Condition Column WatersXBridge C18, 3.0 × 150 mm, 3.5 μm particle size Flow rate 0.7 mL/minMobile Phase A 20 mM Ammonium Bicarbonate, pH 9.0 Mobile Phase BAcetonitrile Elution Program Gradient (see Table 35) Injection Volume 10μL Column Temperature 45° C. Detector Wavelength 324 nm

TABLE 35 HPLC instrument gradient profile used for the assay/impurityanalysis of Example 6. Time (min) % Mobile Phase A % Mobile Phase B 0.0095 5 6.00 80 20 28.00 60 40 35.00 0 100 35.10 95 5 38.00 95 5 40.00 85.015.0

Assay values are listed in Table 36 for Dasatinib:EUDRAGIT L100-55 ASDsand in Table 37 for Dasatinib:METHOCEL E5 ASDs at t=0 and at eachstability time point. These reported assay values are corrected for themeasured water content of the sample.

TABLE 36 Assay data for the Dasatinib:EUDRAGIT L100-55 ASDs of Example6, stored at 40° C./75% RH through 6 months. Assay Value (% label claim,corrected for water content) Dasatinib:EUDRAGIT L100-55 Time Point 70:3075:25 80:20 85:15 90:10 0 99.3 97.6 97.6 98.6 98.4 2 weeks 99.6 98.598.8 100.5 99.8 1 month 100.7 99.0 99.0 101.4 95.9 2 months 100.6 98.198.5 100.9 99.4 3 months 103.0 101.4 100.0 NA^(a) NA^(a) 6 months 99.698.1 98.3 97.9 99.2 ^(a)data is not available due to method error

TABLE 37 Assay data for the Dasatinib:METHOCEL E5 ASDs of Example 6,stored at 40° C./75% RH through 6 months. Assay Value (% label claim,corrected for water content) Dasatinib:METHOCEL E5 Time Point 70:3075:25 80:20 85:15 90:10 0 100.7 100.3 100.8 97.8 98.0 2 weeks 100.3 99.999.0 100.7 100.5 1 month 102.0 100.8 100.7 106.6 101.0 2 months 101.8100.9 100.1 100.1 99.5 3 months 99.3 97.5 97.4 NA^(a) NA^(a) 6 months100.8 100.0 99.2 97.9 97.8 ^(a)data is not available due to method error

Measured total impurities are reported in Table 38 forDasatinib:EUDRAGIT L100-55 ASDs and in Table 39 for Dasatinib:METHOCELE5 ASDs.

TABLE 38 Total impurities data for the Dasatinib:EUDRAGIT L100-55 ASDsof Example 6, stored at 40° C./75% RH through 6 months. Total Impurities(% Area) Dasatinib:EUDRAGIT L100-55 Time Point 70:30 75:25 80:20 85:1590:10 0 0.17 0.17 0.16 0.17 0.17 2 weeks 0.23 0.22 0.21 0.22 0.22 1month 0.31 0.29 0.34 0.34 0.28 2 months 0.44 0.43 0.39 0.36 0.36 3months 0.59 0.53 0.52 NA^(a) NA^(a) 6 months 0.79 0.77 0.66 0.51 0.52^(a)data is not available due to method error

TABLE 39 Total impurities data for the Dasatinib:METHOCEL E5 ASDs ofExample 6, stored at 40° C./75% RH through 6 months. Total Impurities (%Area) Dasatinib:METHOCEL E5 Time Point 70:30 75:25 80:20 85:15 90:10 00.17 0.17 0.14 0.17 0.17 2 weeks 0.21 0.20 0.20 0.24 0.24 1 month 0.280.36 0.36 0.28 0.33 2 months 0.41 0.42 0.40 0.40 0.41 3 months 0.58 0.540.50 NA^(a) NA^(a) 6 months 0.72 0.74 0.75 0.47 0.51 ^(a)data is notavailable due to method error

Based on the assay and total impurities data, it can be concluded thatthe ASDs exhibited acceptable chemical stability under acceleratedconditions throughout the stability study.

Example 7. In Vitro Dissolution of Tablets Comprising Dasatinib ASDs

A study was performed to investigate the in vitro dissolutionperformance of tablets comprising ASDs of the disclosure, in a varietyof biorelevant dissolution media. SPRYCEL, the reference listed drug,was also included in the study as a benchmark, in the form of 100 mgimmediate-release tablets.

Test tablets containing 100 mg dasatinib (in the form ofDasatinib:EUDRAGIT L100-55 ASD or Dasatinib:METHOCEL E5 ASD) wereprepared using appropriate ASDs, as follows. ASDs were first preparedaccording to the method given in Example 1, at various drug loads(drug:polymer ratios of 60:40, 70:30, and 80:20). Granules were thenformed by dry granulation of the ASD with FUJICALIN, AVICEL PH-105,VIVASOL, AEROSIL R972, and magnesium stearate. Suitable quantities ofthe dry components were bag-blended and then roller-compacted to provideribbons. Ribbons were processed through an oscillating granulator andsieved to provide suitably sized granules (20-24 mesh).

Then, a tableting formulation was prepared using approximately 80% (w/w)granules along with suitable quantities of AVICEL PH-102, VIVASOL,AEROSIL R972, and magnesium stearate. The formulation components werethoroughly v-blended, and then tableted using a tablet press to providetest tablets containing 100 mg dasatinib (“Dasatinib ASD Tablet”).

For the dissolution testing, the biorelevant dissolution media includedthe following:

Medium A: pH 4 Acetate buffer (50 mM) with 1% Triton X-100;

Medium B: pH 5.8 Fed-State Simulated Intestinal Fluid (“FeSSIF”);

Medium C: pH 5.5 Acetate buffer (50 mM).

The composition of Medium B is given in Table 40.

TABLE 40 Composition of Medium B: pH 5.8 FeSSIF. Component ConcentrationTaurocholate  10 mM Phospholipids  2 mM Oleate  0.8 mM Glycerolmonooleate  5 mM Sodium 218 mM Chloride 125 mM Maleic acid  55 mM

For the dissolution tests, a Vankel model VK7000 dissolution bath wasfitted with a USP Apparatus II system equipped with 1000-mL vessels andpaddles (60 rpm). The vessels were charged with one of the dissolutionmedia (A, B, or C), and the media equilibrated to 37° C. A sample(Dasatinib ASD Tablet or SPRYCEL) was introduced into each vessel att=0. Sampling timepoints were at t=10 min, 15 min, 30 min, and 45 min.At sampling timepoints, a sample was pulled from each vessel using asyringe and stainless steel cannula fitted with 10 μm full flow filter.Samples were immediately filtered through 0.2 μm nylon filter and thendiluted 1:1 (v/v) with a 50:50 ethanol:methanol (v/v) mixture.

Samples were subsequently analyzed by HPLC using either an Agilent 1200HPLC or a Waters Alliance e2695 HPLC. The instrument and measurementconditions are specified in Table 41 and the gradient profile in Table42.

TABLE 41 HPLC instrument and measurement conditions used for thedissolution concentration analysis of Example 7. Parameter ConditionColumn Waters XBridge C18, 3.0 × 150 mm, 3.5 μm particle size Flow rate0.8 mL/min Mobile Phase A 20 mM Ammonium Bicarbonate, pH 9.0 MobilePhase B Acetonitrile Elution Program Gradient (see Table 42) InjectionVolume 10 μL Column Temperature 45° C. Detector Wavelength 324 nm

TABLE 42 HPLC instrument gradient profile used for the dissolutionconcentration analysis of Example 7. Time (min) % Mobile Phase A %Mobile Phase B  0.00 71 29 10.00 71 29 11.00  0 100 12.00  0 100 12.0171 29 14.00 71 29

The resulting dissolution curves are shown in FIGS. 10-13. FIG. 10 showsthe dissolution curves obtained at pH 4 (Medium A) for tabletscomprising Dasatinib:EUDRAGIT L100-55 ASDs. FIG. 11 shows dissolutioncurves obtained at pH 4 (Medium A) for tablets comprisingDasatinib:METHOCEL E5 ASDs. For both ASD systems, the ASDs having a drugload of 70% or greater performed as well or better (i.e., faster and/ormore complete dissolution) than the SPRYCEL reference. In contrast, anASD having a drug load of 60% did not perform as well as the SPRYCELreference.

FIG. 12 shows dissolution curves obtained with the pH 5.8 FeSSIF (MediumB) for tablets comprising Dasatinib:EUDRAGIT L100-55 ASD at 60% and 80%drug load, and for tablets comprising Dasatinib:METHOCEL E5 ASD at 80%drug load. Each of the ASD tablets performed better than the SPRYCELreference under this condition.

FIG. 13 shows dissolution curves obtained at pH 5.5 (Medium C) fortablets comprising Dasatinib:EUDRAGIT L100-55 ASD at 80% drug load, andfor tablets comprising Dasatinib:METHOCEL E5 ASD at 80% drug load. Eachof the ASD tablets performed better than the SPRYCEL reference underthis condition.

Taken as a whole, these data support the conclusion that the ASDs of thedisclosure provide enhanced solubility in biorelevant media underconditions of elevated pH relative to normal fasted gastric pH. Thisindicates that the ASDs are likely to provide enhanced in vivobioavailability at elevated pH as compared to a formulation comprisingcrystalline dasatinib.

Example 8. In Vivo Pharmacokinetic Study of Tablets Comprising DasatinibASD

A study was performed to evaluate the in vivo pharmacokineticperformance of tablets comprising ASDs of the disclosure. SPRYCEL, thereference listed drug, was also included in the study as a benchmark, inthe form of 100 mg immediate-release tablets.

The test tablet was the Dasatinib ASD Tablet from Example 5. SPRYCEL wasincluded in the study as the reference product, in the form of 100 mgimmediate-release tablets.

The human study employed a balanced, two-treatment, four period, twosequence, single dose, fully replicated crossover design. Separatestudies were done under fasted and fed conditions. (It should be notedthat the two studies were done using different sets of subjects.Absorption of dasatinib is observed to have a high degree ofinter-subject variability.)

Subjects were randomly divided as to the order in which they wouldreceive the test product (Dasatinib ASD Tablet) and the referenceproduct (SPRYCEL tablet) in the study periods. There was a washoutperiod of at least 7 days between the periods.

In the fasted study, subjects were fasted overnight for at least 10hours before administration and for at least 4 hours afteradministration in each study period. Doses were administered with a240-mL portion of water.

In the fed study, subjects were fasted overnight for at least 10 hours,and then were fed a high-fat, high-calorie breakfast starting 30 minutesprior to administration. Subjects then did not eat again for at least 4hours after administration in each study period. Doses were administeredwith a 240-mL portion of water.

Plasma samples were taken within one hour prior to dosing. Post-doseplasma samples were taken at suitable timepoints for evaluating thepharmacokinetic profile, up to 24 hours. At least 18 subjects completedeach period of each study.

Plasma samples were analyzed for dasatinib content. Pharmacokineticparameters were calculated from the data. Calculated pharmacokineticparameters are presented in Table 43 for the fasted study (n=19) andTable 44 for the fed study (n=18).

TABLE 43 Calculated pharmacokinetic parameters under fasted conditionsfor Example 8. Mean (untransformed) ± SD (CV %) Within-Subject DasatinibASD Variability (S_(WR)) Parameters Tablet SPRYCEL tablet SPRYCEL tabletAUC₀_inf 718.8 ± 152.0 657.9 ± 222.1 0.2359 (ng × hr/mL) (21.1) (33.8)AUC_(last) 697.9 ± 149.9 602.4 ± 252.3 0.2442 (ng × hr/mL) (21.4) (41.8)C_(max) (ng/mL) 168.6 ± 50.4  154.8 ± 66.2  0.3814 (29.9) (42.8) t_(max)(hr) 2.2 ± 1.1 1.7 ± 1.1 n/a K_(el) (1/h) 0.155 ± 0.030 0.150 ± 0.041n/a t_(1/2) (hr) 4.6 ± 0.9 5.0 ± 1.5 n/a K_(el) = elimination rateconstant n/a = not applicable

TABLE 44 Calculated pharmacokinetic parameters under fed conditions forExample 8. Mean (untransformed) ± SD (CV %) Within-Subject Dasatinib ASDVariability (S_(WR)) Parameters Tablet SPRYCEL tablet SPRYCEL tabletAUC₀_inf 444.8 ± 99.1  454.1 ± 99.3  0.0962 (ng × hr/mL) (22.3) (21.9)AUC_(last) 419.5 ± 95.1  426.5 ± 94.9  0.0991 (ng × hr/mL) (22.7) (22.3)C_(max) (ng/mL) 75.4 ± 25.0 79.6 ± 20.2 0.1418 (33.1) (25.4) t_(max)(hr) 2.979 ± 1.524 2.665 ± 1.552 n/a K_(el) (1/h) 0.144 ± 0.040 0.137 ±0.036 n/a t_(1/2) (hr) 5.200 ± 1.452 5.408 ± 1.364 n/a K_(el) =elimination rate constant n/a = not applicable

For any log-transformed parameter where the within-subject SD for thereference product (S_(WR))≥0.294, the Scaled Average Bioequivalence(SABE) method was used. The upper 95% confidence bound on the linearizedSABE statistic was calculated. For those log-transformed parameterswhere the within-subject SD for the reference product (S_(WR))≤0.294,the Average Bioequivalence (ABE) method was used.

Based on the statistical analysis for the fasted study, the estimated90% confidence interval for log transformed pharmacokinetic parametersAUC_(last) was not within the acceptance criteria of 80-125%. Thus, itwas concluded that the test product (Dasatinib ASD Tablet) was notbioequivalent to the reference product (SPRYCEL tablet) under fastedconditions. With respect to C_(max), the within-subject variability forthe reference product was significant, which indicated the use of ScaledAverage Bioequivalence (SABE) method for this parameter rather than theAverage Bioequivalence (ABE) method.

Based on the statistical analysis for the fed study, the estimated 90%confidence interval for the ratio of geometric means of test andreference products for C_(max), AUC_(last) and AUC_(0-inf) fall withinthe bioequivalence limit of 80-125% under fed conditions. Thus, it wasconcluded that the test product (Dasatinib ASD Tablet) was bioequivalentto the reference product (SPRYCEL tablet) under fed conditions.

It can further be seen that the test product (Dasatinib ASD Tablet)exhibited a variability, designated by the coefficient of variation (CV,expressed in percent), that was as good or better than the referenceproduct (SPRYCEL tablet) under all conditions for most parameters. Underfed conditions, the variability was quite comparable for test andreference products for all relevant parameters C_(max), AUC_(last), andAUC_(0-inf). Under fasted conditions, the variability was significantlyimproved for the test product for all relevant parameters C_(max),AUC_(last), and AUC_(0-inf) as compared to the reference product.

Furthermore, the test product (Dasatinib ASD Tablet) exhibited a similarvariability for both the fasted and fed state, which is in contrast tothe reference product, which exhibited a significantly highervariability under fasted conditions.

The foregoing description is given for clearness of understanding only,and no unnecessary limitations should be understood therefrom. Variousmodifications and alterations to this disclosure will become apparent tothose skilled in the art without departing from the scope and spirit ofthis disclosure. It should be understood that this disclosure is notintended to be unduly limited by the illustrative embodiments andexamples set forth herein, and such examples and embodiments arepresented by way of example only.

Reference throughout this specification to “one embodiment,” “anembodiment,” “certain embodiments,” or “some embodiments,” etc., meansthat a particular feature, configuration, composition, or characteristicdescribed in connection with the embodiment is included in at least oneembodiment of the disclosure. Thus, the appearances of such phrases invarious places throughout this specification are not necessarilyreferring to the same embodiment of the disclosure. Furthermore, theparticular features, configurations, compositions, or characteristicsmay be combined in any suitable manner in one or more embodiments.

Throughout the specification, where compositions are described asincluding components or materials, it is contemplated that thecompositions can also consist essentially of, or consist of, anycombination of the recited components or materials, unless describedotherwise. Likewise, where methods are described as including particularsteps, it is contemplated that the methods can also consist essentiallyof, or consist of, any combination of the recited steps, unlessdescribed otherwise.

The practice of a method disclosed herein, and individual steps thereof,can be performed manually and/or with the aid of or automation providedby electronic equipment. Although processes have been described withreference to particular embodiments, a person of ordinary skill in theart will readily appreciate that other ways of performing the actsassociated with the methods may be used. For example, the order ofvarious steps may be changed without departing from the scope or spiritof the method, unless described otherwise. In addition, some of theindividual steps can be combined, omitted, or further subdivided intoadditional steps.

The term “comprises” and variations such as “comprises” and “comprising”do not have a limiting meaning where these terms appear in thedescription and claims. Such terms will be understood to imply theinclusion of a stated step or element or group of steps or elements butnot the exclusion of any other step or element or group of steps orelements.

By “consists of” (or similarly “consisting of”) is meant including, andlimited to, whatever follows the phrase “consists of.” Thus, the phrase“consists of” in dictates that the listed elements are required ormandatory, and that no other elements may be present. By “consistsessentially of” (or similarly “consisting essentially of”) is meantincluding any elements listed after the phrase, and limited to otherelements that do not interfere with or contribute to the activity oraction specified in the disclosure for the listed elements. Thus, thephrase “consists essentially of” indicates that the listed elements arerequired or mandatory, but that other elements are optional and may ormay not be present depending upon whether or not they materially affectthe activity or action of the listed elements.

The words “preferred” and “preferably” refer to embodiments of thedisclosure that may afford certain benefits, under certaincircumstances. However, other embodiments may also be preferred, underthe same or other circumstances. Furthermore, the recitation of one ormore preferred embodiments does not imply that other embodiments are notuseful, and is not intended to exclude other embodiments from the scopeof the disclosure.

In this application, terms such as “a,” “an,” and “the” are not intendedto refer to only a singular entity, but include the general class ofwhich a specific example may be used for illustration. The terms “a,”“an,” and “the” are used interchangeably with the term “at least one.”The phrases “at least one of” and “comprises at least one of” followedby a list refer to any one of the items in the list and any combinationof two or more items in the list.

As used herein, the term “or” is generally employed in its usual senseincluding “and/or” unless the content clearly dictates otherwise. Theterm “and/or” means one or all of the listed elements or a combinationof any two or more of the listed elements (e.g., preventing and/ortreating an affliction means preventing, treating, or both treating andpreventing further afflictions).

Also herein, all numbers are assumed to be modified by the term “about”and preferably by the term “exactly.” As used herein in connection witha measured quantity, the term “about” refers to that variation in themeasured quantity as would be expected by the skilled artisan making themeasurement and exercising a level of care commensurate with theobjective of the measurement and the precision of the measuringequipment used. Herein, “up to” a number (e.g., up to 50) includes thenumber (e.g., 50). Also herein, the recitations of numerical ranges byendpoints include all numbers subsumed within that range as well as theendpoints (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.)and any sub-ranges (e.g., 1 to 5 includes 1 to 4, 1 to 3, 2 to 4, etc.).

The complete disclosures of the patents, patent documents, andpublications cited herein are incorporated by reference in theirentirety as if each were individually incorporated. To the extent thatthere is any conflict or discrepancy between the present disclosure andthe disclosure in any document that is incorporated by reference, thisdisclosure as written will control.

What is claimed is:
 1. A pharmaceutical composition comprising an amorphous solid dispersion; wherein the amorphous solid dispersion consists essentially of dasatinib, a methacrylic acid and ethyl acrylate copolymer that exhibits pH-dependent solubility, and optionally one or more functional components selected from the group consisting of antioxidants, wetting agents, and solubilizers; and wherein the dasatinib and the copolymer are present in the amorphous solid dispersion in a w/w ratio of 30:70 to 95:5 (dasatinib:copolymer).
 2. The pharmaceutical composition of claim 1, wherein the copolymer is insoluble in an aqueous medium at pH of 5 or lower, and soluble in an aqueous medium at pH 5.5 or greater.
 3. The pharmaceutical composition of claim 1, wherein the amorphous solid dispersion consists essentially of dasatinib and the copolymer.
 4. The pharmaceutical composition of claim 3, wherein the copolymer is insoluble in an aqueous medium at pH of 5 or lower, and soluble in an aqueous medium at pH 5.5 or greater.
 5. The pharmaceutical composition of claim 1, wherein the amorphous solid dispersion consists of dasatinib and the copolymer.
 6. The pharmaceutical composition of claim 5, wherein the copolymer is insoluble in an aqueous medium at pH of 5 or lower, and soluble in an aqueous medium at pH 5.5 or greater.
 7. The pharmaceutical composition of claim 1, wherein the dasatinib and the copolymer are present in the amorphous solid dispersion in a w/w ratio of 40:60 to 70:30 (dasatinib:copolymer).
 8. The pharmaceutical composition of claim 1, wherein the amorphous solid dispersion includes one or more functional components selected from the group consisting of antioxidants, wetting agents, and solubilizers.
 9. The pharmaceutical composition of claim 1, wherein the one or more functional components includes one or more antioxidants that are present in an amount of 0.001% to 2% by weight of the amorphous solid dispersion.
 10. The pharmaceutical composition of claim 9, wherein the one or more antioxidants includes acetylcysteine, ascorbyl palmitate, butylated hydroxyanisole (“BHA”), butylated hydroxytoluene (“BHT”), monothioglycerol, potassium nitrate, sodium ascorbate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium bisulfate, vitamin E or a derivative thereof, propyl gallate, ethylenediaminetetraacetic acid (“EDTA”) or a salt thereof, diethylenetriaminepentaacetic acid (“DTPA”), bismuth sodium triglycollamate, or a combination thereof.
 11. The pharmaceutical composition of claim 10, wherein the one or more antioxidants are present in an amount of 0.05% to 0.5% by weight of the amorphous solid dispersion.
 12. The pharmaceutical composition of claim 10, wherein the one or more antioxidants comprises butylated hydroxytoluene.
 13. The pharmaceutical composition of claim 10, wherein the one or more antioxidants comprises propyl gallate.
 14. The pharmaceutical composition of claim 1 comprising the amorphous solid dispersion and one or more pharmaceutically acceptable additives.
 15. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is a solid dosage form suitable for oral administration.
 16. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is a gastric acid-insensitive composition.
 17. A kit for sale to a user, the kit comprising a pharmaceutical composition and a package insert; wherein the pharmaceutical composition comprises an amorphous solid dispersion, the amorphous solid dispersion consisting essentially of dasatinib, a methacrylic acid and ethyl acrylate copolymer that exhibits pH-dependent solubility, and optionally one or more functional components selected from the group consisting of antioxidants, wetting agents, and solubilizers; and wherein the dasatinib and the copolymer are present in the amorphous solid dispersion in a w/w ratio of 30:70 to 95:5 (dasatinib:copolymer).
 18. The kit of claim 17, wherein the package insert informs the user that the pharmaceutical composition can be co-administered with a gastric acid-reducing agent.
 19. The kit of claim 17, wherein the package insert informs the user that the pharmaceutical composition can be co-administered with H₂ antagonists or proton pump inhibitors.
 20. The kit of claim 17, wherein the package insert does not comprise a warning that the pharmaceutical composition should not be co-administered with H₂ antagonists or proton pump inhibitors.
 21. The kit of claim 17, wherein the package insert informs the user that the pharmaceutical composition can be suitably administered if the user has chronically elevated gastric pH.
 22. The kit of claim 17, wherein the package insert informs the user that the pharmaceutical composition can be suitably administered if the user has been diagnosed with or is afflicted by achlorhydria or hypochlorhydria.
 23. The kit of claim 17, wherein the package insert informs the user that the pharmaceutical composition can be suitably administered if the user has been diagnosed with or is afflicted by Helicobacter pylori infection.
 24. The kit of claim 17, wherein the copolymer is insoluble in an aqueous medium at pH of 5 or lower, and soluble in an aqueous medium at pH 5.5 or greater.
 25. The kit of claim 17, wherein the dasatinib and the copolymer are present in the amorphous solid dispersion in a w/w ratio of 40:60 to 70:30 (dasatinib:copolymer).
 26. The kit of claim 17, wherein the amorphous solid dispersion includes one or more functional components selected from the group consisting of antioxidants, wetting agents, and solubilizers.
 27. The kit of claim 17, wherein the one or more functional components includes one or more antioxidants that are present in an amount of 0.001% to 2% by weight of the amorphous solid dispersion.
 28. The kit of claim 17, wherein the one or more antioxidants includes acetylcysteine, ascorbyl palmitate, butylated hydroxyanisole (“BHA”), butylated hydroxytoluene (“BHT”), monothioglycerol, potassium nitrate, sodium ascorbate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium bisulfate, vitamin E or a derivative thereof, propyl gallate, ethylenediaminetetraacetic acid (“EDTA”) or a salt thereof, diethylenetriaminepentaacetic acid (“DTPA”), bismuth sodium triglycollamate, or a combination thereof.
 29. The kit of claim 17, comprising the amorphous solid dispersion and one or more pharmaceutically acceptable additives.
 30. The kit of claim 17, wherein the pharmaceutical composition is a solid dosage form suitable for oral administration. 